Amide compounds and medicinal use thereof

ABSTRACT

The present invention relates to a compound of the formula                  
 
wherein R 1  is substituted aryl, heteroaryl and the like, R 2  and R 3  are hydrogen, alkyl, halogen, hydroxyl group and the like, Q is N, CH and the like, W is hydrogen, alkyl, hydroxycarbonylalkyl and the like, X is halogen, cyano, nitro, amino and the like, X′ is hydrogen, halogen, cyano, nitro, and Y is alkyl, hydroxyl group, alkoxy, mercapto and the like and a salt thereof, and a medicine containing the said compound. The compound of the present invention shows a superior inhibitory effect on activated lymphocytes proliferation and is useful as an agent for the prophylaxis or treatment of various autoimmune diseases.

This application is 371 application of PCT/JP00/00767 filed Feb. 10,2000.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an amide compound useful as a medicine,particularly as an agent for the prophylaxis or treatment of autoimmunedisease, and its use as a medicine.

BACKGROUND

Autoimmune diseases are considered to be induced by autoreactivityacquired by lymphocytes that originally does not respond to themselves,or by incomplete removal of autoreactivated lymphocytes in the thymusand the like. In particular, rheumatoid arthritis (RA) is considered tobe induced by immune response of lymphocytes, particularly T cells and Bcells, against type II collagen that mostly exists in one's own joints.The disease gets serious because it accompanies infiltration of T cellsand B cells into the joints, activation and proliferation of these cellsin the joints and, when it advances, abnormal proliferation ofsynoviocytes in the joints to result in articular destruction. Because anumber of activated lymphocytes infiltrate into articular tissues of RApatients, activated lymphocytes are considered to play an important rolein the formation and advance of the disease state of RA.

In general terms, it is known that when lymphocytes are activated byantigen, type 1 helper T cells (Th1 cell) in the lymphocytes producescytokines such as interleukin 2 (IL-2), interferon γ (IFN-γ) and thelike, and the produced IL-2 and IFN-γ cause growth and division oflymphocytes, particularly T cells. Despite the presence of a greatnumber of activated lymphocytes in the articular tissues of RA patients,IL-2 level is extremely low, which has produced a presumption that alymphocyte growth factor should be present besides IL-2 (Journal ofExperimental Medicine, vol. 168, p. 1573, 1988).

Recently, interleukin 15 (IL-15) was cloned as a new cytokine thatpromotes growth and differentiation of lymphocytes (T cells or B cells)(Science, vol. 264, p 965, 1994). The IL-15 receptor has been clarifiedto consist of α chain specific to IL-15, β chain common to IL-15 andIL-2, and γ chain common to the receptors of IL-15, IL-2, IL-4, IL-7,IL-9 and IL-13 (EMBO Journal, vol. 13, p. 2822, 1994; EMBO Journal, vol.14, p. 3654, 1995). The presence of a signal transduction pathway viatyrosin kinase (represented by JAK1 and JAK3) in the downstream of βchain and γ chain has been also uncovered (Science, vol. 266, p. 1782,1994). It is expected, therefore, that the pharmacological activityinduced by the binding of IL-15 and IL-15 receptor is the promotion ofproliferation of lymphocytes, and is almost of the same nature as thebinding of IL-2 and IL-2 receptor. It has been reported that the IL-2,IL-9-producing cells are T cells, particularly helper T cells activatedby antigen, the IL-7-producing cells are mostly stroma cells, andIL-15-producing cells are macrophages, dendritic cells, synoviocytes andthe like (Science, vol. 264, p. 965, 1994). A recent report hasdocumented that synovial fluid of RA patients has a markedly highconcentration of IL-15, which suggests the important role of IL-15 as agrowth factor for the proliferation of activated lymphocytes in thejoints in RA. In addition, there is a report on many activities of IL-15besides promotion of proliferation of the activated lymphocytes, such aspromotion of migration of T cells toward inflammatory sites, activationof memory T cells, promotion of production of inflammatory cytokinessuch as tumor necrosis factor (TNF)-αand the like, and other activities(Nature medicine, vol. 3, p. 189, 1997). It is being elucidated thatIL-15 plays an important role in the onset and development of variousautoimmune diseases such as Crohn's diseases, lupus-nephritis insystemic lupus erythematosus and the like.

From the foregoing, it is considered that, for the improvement ofsymptoms of autoimmune diseases represented by RA, inhibition ofproliferation of IL-15-dependent activated lymphocytes is particularlyeffective.

Conventionally, a therapeutic agent for autoimmune diseases,particularly RA, has been a gold compound, penicillamine, bucillamine,azathioprine, cyclophosphamide, methotrexate and the like. These inhibitproliferation of synoviocytes in the joints. Due to their antagonisticinhibitory action in nucleic acid metabolism, however, the long-term useof the agent is associated with highly frequent occurrence of sideeffects, such as hematopoietic injury, digestive system disorder and thelike. Combined with easy infectivity and the like caused by the agents,they are not therapeutically satisfactory. While corticosteroid iseffective for these diseases, it is associated with serious sideeffects, such as moon face, hypoadrenalism, osteonecrosis of femoralhead and the like. Furthermore, leflunomide approved as an antirheumaticdrug in the US has been reported to show a long half-life of blooddisappearance despite its superior therapeutic effect, causing sideeffects such as digestive system disorder, liver disorder, eruption andthe like (The Lancet, vol. 353, pp. 259–266, 1999), and a clinicallymore superior therapeutic agent is desired.

Thus, there is a strong demand for a therapeutic agent for autoimmunediseases such as RA and the like, which shows a superior therapeuticeffect as compared to conventional pharmaceutical agents and whichcauses less side effects.

As mentioned above, the proliferation of activated lymphocytes inarticular tissue is deeply involved in the progress of arthritis in RA,and IL-15 is suggested to be responsible for the proliferation ofactivated lymphocytes. Therefore, a compound that inhibits signaltransduction via tyrosine kinase originated from IL-15 receptor (γ chaincommon to IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15) is considered to showa superior effect for the prophylaxis or treatment of autoimmunediseases such as rheumatoid arthritis and the like. In addition to theaforementioned effect, a compound that inhibits production of IL-15itself or production of inflammatory cytokines, such as TNF-α and thelike, which is derived by IL-15, is likely to show a superior effect forthe prophylaxis or treatment of autoimmune diseases such as rheumatoidarthritis and the like. However, there is no report taking note ofIL-15, which concerns a compound having an inhibitory effect on theproliferation of activated lymphocytes as a therapeutic agent forautoimmune diseases or as a therapeutic agent for RA.

Bioorganic and Medicinal Chemistry Letters, vol. 8, pp. 2787–2792, 1998discloses a pyrazolecarboxamide compound useful as an immunosuppressantagent. As phenylpyrazolecarboxamide having similar structure,JP-A-52–87168 discloses a compound as an antimicrobial agent, WO97/11690discloses a compound for treating bacterial infection in which atherapeutically effective amount of an inhibitor of global regulator ofpathogenic gene is administered to mammals. Veshchestva, vol. 23, pp.82–87, 1991 discloses a compound as an agricultural chemical to inhibitgrowth of plants. However, an inhibitory effect on the proliferation ofactivated lymphocytes taking note of IL-15 on these compounds is notdisclosed at all.

In view of the above, the present inventors have conducted intensivestudies and found that an amide compound of the following formula and apharmaceutically acceptable salt thereof suppress cytokine response thatmay induce proliferation, differentiation and the like of various cellsresponsible for immunity, such as lymphocytes (T cells, B cells),macrophages and the like, by the addition of a cytokine, such as IL-2,IL-4, IL-7, IL-9, IL-13, IL-15 and the like, in the presence or absenceof an antigen or mitogen. In particular, they have found that the abovecompound and its salt inhibit IL-15-dependent proliferation of activatedlymphocytes and production of inflammatory cytokine derived by IL-15,namely, IL-1, IL-6, IL-12, IL-15, IL-18, TNF-α and the like, whichresulted in the completion of the present invention.

DISCLOSURE OF THE INVENTION

Accordingly, the present invention provides the following.

-   [1] An amide compound of the formula    wherein-   R¹ is substituted aryl, arylalkyl, optionally substituted    heteroaryl, heteroarylalkyl or cycloalkyl,-   R² and R³ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁴ (wherein R⁴ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X is halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy,    alkoxycarbonyl, carbamoyl, alkenyl, alkynyl or haloalkyl,-   X′ is hydrogen, halogen, cyano or nitro, and-   Y is alkyl, hydroxyalkyl, hydroxycarbonylalkyl, optionally    substituted aminoalkyl, hydroxyl group, alkoxy, haloalkoxy, aryloxy,    cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally    substituted aminoalkoxy, mercapto, alkylthio, hydroxyalkylthio,    hydroxycarbonylalkylthio, optionally substituted aminoalkylthio, a    group O-Het (wherein Het is optionally substituted saturated    heterocycle having hetero atom selected from oxygen atom and    nitrogen atom) or a group N(Z²) (Z³) (wherein Z² and Z³ are the same    or different and each is hydrogen, alkyl, hydroxyalkyl or    aminoalkyl, or Z² and Z³ form, together with the adjacent nitrogen    atom, cyclic amine optionally having one or two atoms from oxygen    atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [2] The amide compound of the above-mentioned [1], which has the    formula    wherein-   R¹ is substituted aryl, arylalkyl, optionally substituted    heteroaryl, heteroarylalkyl or cycloalkyl,-   R² and R³ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁴ (wherein R⁴ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X is halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy,    alkoxycarbonyl, carbamoyl, alkenyl, alkynyl or haloalkyl,-   Y is alkyl, hydroxyalkyl, hydroxycarbonylalkyl, optionally    substituted aminoalkyl, hydroxyl group, alkoxy, haloalkoxy, aryloxy,    cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally    substituted aminoalkoxy, mercapto, alkylthio, hydroxyalkylthio,    hydroxycarbonylalkylthio, optionally substituted aminoalkylthio, a    group O-Het (wherein Het is optionally substituted saturated    heterocycle having hetero atom selected from oxygen atom and    nitrogen atom) or a group N(Z²)(Z³) (wherein Z² and Z³ are the same    or different and each is hydrogen, alkyl, hydroxyalkyl or    aminoalkyl, or Z² and Z³ form, together with the adjacent nitrogen    atom, cyclic amine optionally having one or two atoms from oxygen    atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [3] The amide compound of the above-mentioned [2], which has the    formula    wherein-   R¹ is substituted aryl, arylalkyl, optionally substituted    heteroaryl, heteroarylalkyl or cycloalkyl,-   R² and R³ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁴ (wherein R⁴ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X is halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy,    alkoxycarbonyl, carbamoyl, alkenyl, alkynyl or haloalkyl, and-   Y is alkyl, hydroxyalkyl, hydroxycarbonylalkyl, optionally    substituted aminoalkyl, hydroxyl group, alkoxy, haloalkoxy, aryloxy,    cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally    substituted aminoalkoxy, mercapto, alkylthio, hydroxyalkylthio,    hydroxycarbonylalkylthio, optionally substituted aminoalkylthio, a    group O-Het (wherein Het is optionally substituted saturated    heterocycle having hetero atom selected from oxygen atom and    nitrogen atom) or a group N(Z²) (Z³) (wherein Z² and Z³ are the same    or different and each is hydrogen, alkyl, hydroxyalkyl or    aminoalkyl, or Z² and Z³ form, together with the adjacent nitrogen    atom, cyclic amine optionally having one or two atoms from oxygen    atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [4] The amide compound of the above-mentioned [3], which has the    formula    wherein-   R¹ is substituted aryl, arylalkyl, optionally substituted    heteroaryl, heteroarylalkyl or cycloalkyl,-   R² and R³ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁴ (wherein R⁴ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X¹ is halogen, cyano, nitro, carboxy, alkoxycarbonyl or alkynyl, and-   Y¹ is alkoxy, haloalkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy,    optionally substituted aminoalkoxy, optionally substituted    aminoalkylthio, a group O-Het (wherein Het is optionally substituted    saturated heterocycle having hetero atom selected from oxygen atom    and nitrogen atom) or a group N(Z²)(Z³) (wherein Z² and Z³ are the    same or different and each is hydrogen, alkyl, hydroxyalkyl or    aminoalkyl, or Z² and Z³ form, together with the adjacent nitrogen    atom, cyclic amine optionally having one or two atoms from oxygen    atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [5] The amide compound of the above-mentioned [4], which has the    formula    wherein-   R^(1a) is substituted aryl, arylalkyl or optionally substituted    heteroaryl,-   R^(1a) and R^(3a) are the same or different and each is hydrogen or    alkyl,-   Q¹ is nitrogen atom or a group C—R^(4a) (wherein R^(4a) is hydrogen    or alkyl),-   W¹ is hydrogen, alkyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl,    and-   Y² is alkoxy, optionally substituted aminoalkoxy, optionally    substituted aminoalkylthio or a group N(Z^(2a)) (Z^(3a)) (wherein    Z^(2a) and Z^(3a) form, together with the adjacent nitrogen atom,    cyclic amine optionally having one or two atoms from oxygen atom,    sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [6] The amide compound of [1] above, which is a member selected from    the group consisting of-   (1)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide,-   (2)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (3)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxamide,-   (4)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-N,3-dimethylpyrazole-4-carboxamide,-   (5)    N-(3-cyano-4-neopentyloxyphenyl)-5-chloro-1-(4-fluorophenyl)pyrazole-4-carboxamide,-   (6)    N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine,-   (7)    4-[N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]amino]butyric    acid,-   (8)    N-(3-cyano-4-piperidinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (9)    N-[3-cyano-4-(4-hydroxypiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (10)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrazole-4-carboxamide,-   (11)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide,-   (12)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (13)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (14)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide,-   (15)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxamide,-   (16)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,-   (17)N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(2,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,-   (18)    N-{3-cyano-4-[4-(2-hydroxyethyl)homopiperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (19)    N-{3-cyano-4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (20)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-3-carboxamide,-   (21)    1-(4-bromophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (22)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide,-   (23)    1-(4-chlorophenyl)-N-(3-cyano-4-piperidinophenyl)-5-methylpyrazole-4-carboxamide,-   (24)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-hydroxypiperidin-1-yl)phenyl]5-methylpyrazole-4-carboxamide,-   (25)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (26)    N-{4-(4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-3-cyanophenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (27)    1-(3,4-dichlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (28)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,-   (29)    1-(3-chloro-4-fluorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (30)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,-   (31)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,-   (32)    N-{4-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]-3-cyanophenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide-   (33)    1-(4-chlorophenyl)-N-[3-cyano-(4-morpholinopiperidin-1-yl)phenyl]pyrrole-3-carboxamide,-   (34)    N-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (35)    N-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (36)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (37)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (38)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (39)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-3-carboxamide,-   (40)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)    piperazin-1-yl]phenyl}pyrrole-3-carboxamide,-   (41)    1-(3,4-dichlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (42)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (43)    1-(3,4-dichlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (44)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (45)    1-(4-chlorophenyl)-N-(3-cyano-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}phenyl)-5-methylpyrazole-4-carboxamide,-   (46)    1-(4-chlorophenyl)-N-[3-cyano-4-(1,4-dioxa-8-azaspiro[4,5]deca-8-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (47)    1-(4-bromophenyl)-N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-5-methylpyrazole-4-carboxamide,-   (48)    N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (49)    N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-1-(4-fluorophenyl)pyrrole-3-carboxamide,-   (50)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide,-   (51)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide,-   (52)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxamide,-   (53)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-thiomorpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (54)    1-(4-chlorophenyl)-5-methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-nitrophenyl]pyrazole-4-carboxamide,-   (55)    5-methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-nitrophenyl]-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (56)    N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (57)    1-(4-chlorophenyl)-N-[3-ethynyl-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (58)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(2-phenylethyl)pyrazole-4-carboxamide,-   (59)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-methoxymethoxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (60)    1-(4-chlorophenyl)-N-[3-cyano-4-[4-(2-methoxyethoxy)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide,-   (61)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (62)    N-[3-cyano-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-nitrophenyl)    pyrazole-4-carboxamide,-   (63)    1-(4-bromophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (64)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,-   (65)    1-(3-chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (66)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-(4-methylphenyl)pyrazole-4-carboxamide,-   (67)    1-(3-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-5-methylpyrazole-4-carboxamide,-   (68)    1-(4-chlorophenyl)-N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (69)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-trifluoromethylphenyl)pyrrole-3-carboxamide,-   (70)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)pyrrole-3-carboxamide,-   (71)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-dichlorophenyl)pyrrole-3-carboxamide,-   (72)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dichlorophenyl)pyrrole-3-carboxamide,-   (73)    1-(4-chlorophenyl)-N-{3-ethynyl-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (74)    1-(4-chlorophenyl)-5-methyl-N-{3-(1-propyne)-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}pyrazole-4-carboxamide,-   (75)    1-(4-chlorophenyl)-5-methyl-N-[3-(1-propyne)-4-(4-morpholinopiperidin-1-yl)phenyl]pyrazole-4-carboxamide,-   (76)    1-(4-chlorophenyl)-N-{3-ethenyl-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (77)    1-(4-chlorophenyl)-N-[3-ethenyl-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (78)    1-(4-chlorophenyl)-N-[3-iodo-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (79)    N-{3-bromo-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (80)    N-{3-chloro-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (81)    N-{3-chloro-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)    pyrrole-3-carboxamide,-   (82)    N-{3-bromo-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)pyrrole-3-carboxamide,-   (83)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentyloxy)phenyl]-5-methylpyrazole-4-carboxamide,-   (84)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentyloxy)phenyl]pyrrole-3-carboxamide,-   (85)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentylthio)phenyl]-5-methylpyrazole-4-carboxamide,-   (86)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentylthio)phenyl]pyrrole-3-carboxamide,-   (87)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamide,-   (88)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (89)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamide,-   (90)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (91)    1-(4-chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-5-methylpyrazole-4-carboxamide,-   (92)    1-(4-chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]pyrrole-3-carboxamide,-   (93)    N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-5-methyl-1-(3,4-methylenedioxyphenyl)pyrazole-4-carboxamide,-   (94)    N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (95)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (96)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,

(97)N-[3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,

-   (98)    N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (99)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-5-methylpyrazole-4-carboxamide,-   (100)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)pyrrole-3-carboxamide,-   (101)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2,5-dimethylpyrrole-3-carboxamide,-   (102)    1-(4-chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-2,5-dimethylpyrrole-3-carboxamide,    and-   (103)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperazin-1-yl)phenyl]-2,5-dimethylpyrrole-3-carboxamide    or a pharmaceutically acceptable salt thereof.-   [7] A pharmaceutical composition comprising the amide compound of    the above-mentioned [1] to [6] or a pharmaceutically acceptable salt    thereof, and a pharmaceutically acceptable carrier.-   [8] A pharmaceutical agent comprising the amide compound of the    above-mentioned [1] to [6] or a pharmaceutically acceptable salt    thereof.-   [9] An inhibitor on the proliferation of activated lymphocytes    comprising, as an active ingredient, an amide compound of the    formula    wherein-   R⁵ is hydrogen, optionally substituted alkyl, hydroxyalkyl,    aminoalkyl, optionally substituted aryl, arylalkyl, optionally    substituted heteroaryl, heteroarylalkyl or cycloalkyl,-   R⁶ and R⁷ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁸ (wherein R⁸ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X is halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy,    alkoxycarbonyl, carbamoyl, alkenyl, alkynyl or haloalkyl,-   X′ is hydrogen, halogen, cyano or nitro, and-   Y is alkyl, hydroxyalkyl, hydroxycarbonylalkyl, optionally    substituted aminoalkyl, hydroxyl group, alkoxy, haloalkoxy, aryloxy,    cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally    substituted aminoalkoxy, mercapto, alkylthio, hydroxyalkylthio,    hydroxycarbonylalkylthio, optionally substituted aminoalkylthio, a    group O-Het (wherein Het is optionally substituted saturated    heterocycle having hetero atom selected from oxygen atom and    nitrogen atom) or a group N(Z²) (Z³) (wherein Z² and Z³ are the same    or different and each is hydrogen, alkyl, hydroxyalkyl or    aminoalkyl, or Z² and Z³ form, together with the adjacent nitrogen    atom, cyclic amine optionally having one or two atoms from oxygen    atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [10] An inhibitor on the proliferation of activated lymphocytes    comprising the amide compound of the above-mentioned [1]–[6] or a    pharmaceutically acceptable salt thereof as an active ingredient.-   [11] The inhibitor on the proliferation of activated lymphocytes of    the above-mentioned [9] or [10], which is dependent on IL-2, IL-4,    IL-7, IL-9, IL-13 or IL-15.-   [12] A phosphorylation inhibitor of tyrosine kinase involved in the    signal transduction in the downstream of a common β chain that is a    receptor subunit common to IL-15 and IL-2 and/or a common γ chain    that is a receptor subunit common to IL-2, IL-4, IL-7, IL-9, IL-13    and IL-15, which inhibitor comprises the amide compound of the    above-mentioned [1]–[6] or a pharmaceutically acceptable salt    thereof as an active ingredient.-   [13] The cytokine production inhibitor, which comprises the amide    compound of the above-mentioned [1]–[6] or a pharmaceutically    acceptable salt thereof as an active ingredient.-   [14] An IL-2, IL-4, IL-13 or IFN-γ production inhibitor, which    comprises the amide compound of the above-mentioned [1]–[6] or a    pharmaceutically acceptable salt thereof as an active ingredient.-   [15] An IL-1, IL-6, IL-12, IL-15, IL-18 or TNF-α production    inhibitor, which comprises the amide compound of the above-mentioned    [1]–[6] or a pharmaceutically acceptable salt thereof as an active    ingredient.-   [16] A pharmaceutical agent comprising a synthesized low molecular    compound having inhibitory effect on activated lymphocytes    proliferation dependent on IL-2, IL-4, IL-7, IL-9, IL-13 or IL-15.-   [17] An agent for the prophylaxis or treatment of diseases caused by    proliferation of lymphocytes, which agent comprises, as an active    ingredient, a synthesized low molecular compound having inhibitory    effect on activated lymphocytes proliferation dependent on IL-2,    IL-4, IL-7, IL-9, IL-13 or IL-15.-   [18] An agent for the prophylaxis or treatment of diseases caused by    proliferation of lymphocytes, which comprises the amide compound of    the above-mentioned [1]–[6] or a pharmaceutically acceptable salt    thereof as an active ingredient.-   [19] An agent for the prophylaxis or treatment of autoimmune    diseases, which comprises, as an active ingredient, a synthesized    low molecular compound having inhibitory effect on activated    lymphocytes proliferation dependent on IL-2, IL-4, IL-7, IL-9, IL-13    or IL-15.-   [20] An agent for the prophylaxis or treatment of autoimmune    diseases, which comprises, as an active ingredient, the amide    compound of the above-mentioned [1]–[6] or a pharmaceutically    acceptable salt thereof.-   [21] An agent for the prophylaxis or treatment of rheumatoid    arthritis, which comprises, as an active ingredient, the amide    compound of the above-mentioned [1]–[6] or a pharmaceutically    acceptable salt thereof.-   [22] A combination composition comprising the amide compound of the    formula    wherein-   R¹ is substituted aryl, arylalkyl, optionally substituted    heteroaryl, heteroarylalkyl or cycloalkyl,-   R² and R³ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁴ (wherein R⁴ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X is halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy,    alkoxycarbonyl, carbamoyl, alkenyl, alkynyl or haloalkyl,-   X′ is hydrogen, halogen, cyano or nitro, and-   Y is alkyl, hydroxyalkyl, hydroxycarbonylalkyl, optionally    substituted aminoalkyl, hydroxyl group, optionally substituted    alkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy,    hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, mercapto,    alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio, optionally    substituted aminoalkylthio, a group O-Het (wherein Het is optionally    substituted saturated heterocycle having hetero atom selected from    oxygen atom and nitrogen atom) or a group N(Z²)(Z³) (wherein Z² and    Z³ are the same or different and each is hydrogen, alkyl,    hydroxyalkyl or aminoalkyl, or Z² and Z³ form, together with the    adjacent nitrogen atom, cyclic amine optionally having one or two    atoms from oxygen atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof, and one or more    pharmaceutical agents selected from an antirheumatic drug, an    immunosuppressive agent, a steroidal drug and a nonsteroidal    anti-inflammatory drug.-   [23] The combination composition of the above-mentioned [22],    wherein the antirheumatic drug is selected from a gold compound,    penicillamine, bucillamine, lobenzarit, actarit and    salazosulfapyridine.-   [24] The combination composition of the above-mentioned [22],    wherein the immunosuppressive agent is selected from azathioprine,    cyclophosphamide, methotrexate, brequinar sodium, deoxyspergualin,    mizoribine, 2-morpholinoethyl mycophenolate, cyclosporin, rapamycin,    tacrolimus hydrate, leflunomide, OKT-3, anti TNF-α antibody, anti    IL-6 antibody and FTY720.-   [25] The combination composition of the above-mentioned [22],    wherein the steroidal drug is selected from prednisolone,    methylprednisolone, dexamethasone and hydrocortisone.-   [26] The combination composition of the above-mentioned [22],    wherein the nonsteroidal anti-inflammatory drug is selected from    aspirin, indomethacin, indomethacin farnesil, diclofenac sodium,    alclofenac, amfenac sodium, ibuprofen, ketoprofen, loxoprofen    sodium, naproxen, pranoprofen, zaltoprofen, mefenamic acid,    flufenamic acid, tolufenamic acid, phenylbutazone,    ketophenylbutazone, piroxicam, tenoxicam and ampiroxicam.-   [27] An effect enhancer of one or more pharmaceutical agents    selected from an antirheumatic drug, an immunosuppressive agent, a    steroidal drug and a nonsteroidal anti-inflammatory drug, which    enhancer comprises an amide compound of the formula    wherein-   R¹ is substituted aryl, arylalkyl, optionally substituted    heteroaryl, heteroarylalkyl or cycloalkyl,-   R² and R³ are the same or different and each is hydrogen, alkyl,    halogen, hydroxyl group, alkoxy, optionally-substituted amino or    phenyl,-   Q is nitrogen atom or a group C—R⁴ (wherein R¹ is hydrogen, alkyl,    halogen or optionally substituted amino),-   W is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,    hydroxycarbonylalkyl or alkoxycarbonylalkyl,-   X is halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy,    alkoxycarbonyl, carbamoyl, alkenyl, alkynyl or haloalkyl,-   X′ is hydrogen, halogen, cyano or nitro, and-   Y is alkyl, hydroxyalkyl, hydroxycarbonylalkyl, optionally    substituted aminoalkyl, hydroxyl group, optionally substituted    alkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy,    hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, mercapto,    alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio, optionally    substituted aminoalkylthio, a group O-Het (wherein Het is optionally    substituted saturated heterocycle having hetero atom selected from    oxygen atom and nitrogen atom) or a group N(Z²)(Z³) (wherein Z² and    Z³ are the same or different and each is hydrogen, alkyl,    hydroxyalkyl or aminoalkyl, or Z² and Z³ form, together with the    adjacent nitrogen atom, cyclic amine optionally having one or two    atoms from oxygen atom, sulfur atom and nitrogen atom in the ring),    or a pharmaceutically acceptable salt thereof.-   [28] The effect enhancer of the above-mentioned [27], wherein the    antirheumatic drug is selected from a gold compound, penicillamine,    bucillamine, lobenzarit, actarit and salazosulfapyridine.-   [29] The effect enhancer of the above-mentioned [27], wherein the    immunosuppressive agent is selected from azathioprine,    cyclophosphamide, methotrexate, brequinar sodium, deoxyspergualin,    mizoribine, 2-morpholinoethyl mycophenolate, cyclosporin, rapamycin,    tacrolimus hydrate, leflunomide, OKT-3, anti TNF-α antibody, anti    IL-6 antibody and FTY720.-   [30] The effect enhancer of the above-mentioned [27], wherein the    steroidal drug is selected from prednisolone, methylprednisolone,    dexamethasone and hydrocortisone.-   [31] The effect enhancer of the above-mentioned [27], wherein the    nonsteroidal anti-inflammatory drug is selected from aspirin,    indomethacin, indomethacin farnesil, diclofenac sodium, alclofenac,    amfenac sodium, ibuprofen, ketoprofen, loxoprofen sodium, naproxen,    pranoprofen, zaltoprofen, mefenamic acid, flufenamic acid,    tolufenamic acid, phenylbutazone, ketophenylbutazone, piroxicam,    tenoxicam and ampiroxicam.

The present invention aims at providing a synthesized low molecularcompound having an inhibitory effect on the proliferation of activatedlymphocytes taking note of IL-15. The inhibitory effect on theproliferation of activated lymphocytes taking note of IL-15 meansinhibitory effect on activated lymphocytes proliferation dependent onIL-15, and embraces an inhibitory effect on the activated lymphocytesproliferation dependent on IL-2, IL-4, IL-7, IL-9 and IL-13 which arecytokines closely related to IL-15. The present invention also aims atproviding a compound which inhibits signal transduction from an IL-15receptor (β chain common to IL-15 and IL-2, and γ chain common to IL-2,IL-4, IL-7, IL-9, IL-13 and IL-15), inhibits a path via tyrosine kinaseduring the process of the signal transduction, and which inhibitsproduction of IL-15 and inflammatory cytokines (IL-1, IL-6, IL-12,IL-15, IL-18, TNF-α and the like) derived by IL-15. In addition, thesynthesized low molecular compound is able to produce by using a lowmolecular weight organic compound to a method known in the field oforganic synthetic chemistry. The preferable compounds in the presentinvention are compound (I) and compound (I-e), more preferably thecompound (I-a)- compound (I-d). The particularly preferable compoundsare as follows.

-   (1)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide,-   (2)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (3)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxamide,-   (4)    N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-N,3-dimethylpyrazole-4-carboxamide,-   (5)    N-(3-cyano-4-neopentyloxyphenyl)-5-chloro-1-(4-fluorophenyl)pyrazole-4-carboxamide,-   (6)    N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine,-   (7)    4-[N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]amino]butyric    acid,-   (8)    N-(3-cyano-4-piperidinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (9)    N-[3-cyano-4-(4-hydroxypiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (10)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrazole-4-carboxamide,-   (11)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide,-   (12)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (13)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (14)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide,-   (15)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxamide,-   (16)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,-   (17)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(2,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,-   (18)    N-{3-cyano-4-[4-(2-hydroxyethyl)homopiperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (19)    N-{3-cyano-4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (20)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-3-carboxamide,-   (21)    1-(4-bromophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (22)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide,-   (23)    1-(4-chlorophenyl)-N-(3-cyano-4-piperidinophenyl)-5-methylpyrazole-4-carboxamide,-   (24)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (25)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (26)    N-(4-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-3-cyanophenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (27)    1-(3,4-dichlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)    phenyl]-5-methylpyrazole-4-carboxamide,-   (28)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,-   (29)    1-(3-chloro-4-fluorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (30)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,-   (31)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,-   (32)    N-{4-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]-3-cyanophenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide-   (33)    1-(4-chlorophenyl)-N-[3-cyano-(4-morpholinopiperidin-1-yl)phenyl]pyrrole-3-carboxamide,-   (34)    N-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (35)    N-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (36)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (37)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (38)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (39)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-3-carboxamide,-   (40)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}pyrrole-3-carboxamide,-   (41)    1-(3,4-dichlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (42)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (43)    1-(3,4-dichlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (44)    1-(4-chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (45)    1-(4-chlorophenyl)-N-(3-cyano-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}phenyl)-5-methylpyrazole-4-carboxamide,-   (46)    1-(4-chlorophenyl)-N-[3-cyano-4-(1,4-dioxa-8-azaspiro[4,5]deca-8-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (47)    1-(4-bromophenyl)-N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-5-methylpyrazole-4-carboxamide,-   (48)    N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (49)    N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-1-(4-fluorophenyl)pyrrole-3-carboxamide,-   (50)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide,-   (51)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide,-   (52)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxamide,-   (53)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-thiomorpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (54)    1-(4-chlorophenyl)-5-methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-nitrophenyl]pyrazole-4-carboxamide-   (55)    5-methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-nitrophenyl]-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (56)    N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide,-   (57)    1-(4-chlorophenyl)-N-[3-ethynyl-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (58)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(2-phenylethyl)pyrazole-4-carboxamide,-   (59)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-methoxymethoxypiperidin-1-yl)    phenyl]-5-methylpyrazole-4-carboxamide,-   (60)    1-(4-chlorophenyl)-N-[3-cyano-4-[4-(2-methoxyethoxy)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (61)    N-{3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,-   (62)    N-[3-cyano-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-nitrophenyl)pyrazole-4-carboxamide,-   (63)    1-(4-bromophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (64)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,-   (65)    1-(3-chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (66)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-(4-methylphenyl)pyrazole-4-carboxamide,-   (67)    1-(3-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-5-methylpyrazole-4-carboxamide,-   (68)    1-(4-chlorophenyl)-N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (69)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-trifluoromethylphenyl)pyrrole-3-carboxamide,-   (70)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)pyrrole-3-carboxamide,-   (71)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-dichlorophenyl)pyrrole-3-carboxamide,-   (72)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dichlorophenyl)pyrrole-3-carboxamide,-   (73)    1-(4-chlorophenyl)-N-{3-ethynyl-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (74)    1-(4-chlorophenyl)-5-methyl-N-{3-(1-propyne)-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}pyrazole-4-carboxamide,-   (75)    1-(4-chlorophenyl)-5-methyl-N-[3-(1-propyne)-4-(4-morpholinopiperidin-1-yl)phenyl]pyrazole-4-carboxamide,-   (76)    1-(4-chlorophenyl)-N-{3-ethenyl-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,-   (77)    1-(4-chlorophenyl)-N-[3-ethenyl-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (78)    1-(4-chlorophenyl)-N-[3-iodo-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,-   (79)    N-{3-bromo-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (80)    N-{3-chloro-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,-   (81)    N-{3-chloro-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)pyrrole-3-carboxamide,-   (82)    N-{3-bromo-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)pyrrole-3-carboxamide,-   (83)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentyloxy)phenyl]-5-methylpyrazole-4-carboxamide,-   (84)1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentyloxy)phenyl]pyrrole-3-carboxamide,-   (85)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentylthio)phenyl]-5-methylpyrazole-4-carboxamide,-   (86)    1-(4-chlorophenyl)-N-[3-cyano-4-(5-morpholinopentylthio)phenyl]pyrrole-3-carboxamide,-   (87)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamide,-   (88)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (89)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamide,-   (90)    N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (91)    1-(4-chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-5-methylpyrazole-4-carboxamide,-   (92)    1-(4-chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]pyrrole-3-carboxamide,-   (93)    N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-5-methyl-1-(3,4-methylenedioxyphenyl)pyrazole-4-carboxamide,-   (94)    N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (95)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (96)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(3,4-methylenedioxyphenyl)    pyrrole-3-carboxamide,-   (97)    N-[3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (98)    N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamide,-   (99)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-5-methylpyrazole-4-carboxamide,-   (100)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)pyrrole-3-carboxamide,-   (101)    N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2,5-dimethylpyrrole-3-carboxamide,-   (102)    1-(4-chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-2,5-dimethylpyrrole-3-carboxamide,    and-   (103)    1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperazin-1-yl)phenyl]-2,5-dimethylpyrrole-3-carboxamide.

The substituents represented by each symbol in the present specificationare explained in the following.

The aryl of substituted aryl at R¹, R^(1a) and R⁵ means phenyl, naphthyland the like, wherein the substituent is 1 to 3 groups selected fromhalogen (fluorine, chlorine, bromine, iodine), alkyl having 1 to 4carbon atoms (methyl, ethyl, propyl, isopropyl, butyl and the like),alkoxy having 1 to 4 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy,butoxy and the like), cyano, nitro, carboxy, alkylenedioxy having 1 to 4carbon atoms (methylenedioxy, ethylenedioxy, propylenedioxy,1,1-dimethylmethylenedioxy and the like) and haloalkyl having 1 to 4carbon atoms (fluoromethyl, chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl and the like). The preferable substituent isexemplified by halogen, alkyl, alkoxy, haloalkyl, alkylenedioxy andnitro. Examples of substituted aryl include 4-chlorophenyl,3-chlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl,4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 4-cyanophenyl,4-carboxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl,2-chloro-5-trifluoromethylphenyl, 4-nitrophenyl,3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl and the like.

The arylalkyl at R¹, R^(1a) and R⁵ is aryl (phenyl, naphthyl and thelike) substituted with alkyl having 1 to 4 carbon atoms, and isexemplified by phenylmethyl, 2-phenylethyl, 1-phenylethyl,3-phenylpropyl, 4-phenylbutyl and the like.

The heteroaryl of optionally substituted heteroaryl at R¹, R^(1a) and R⁵is a 5 or 6-membered heteroaryl ring having 1 or 2 substituents selectedfrom hetero atoms of nitrogen atom, sulfur atom and oxygen atom. As thesubstituent, alkyl having 1 to 4 carbon atoms, halogen (fluorine,chlorine, bromine and the like) and the like are exemplified. Examplesthereof include pyrimidyl, 4,6-dimethylpyrimidyl, pyridazinyl,6-chloropyridazinyl, thienyl, 5-methylthienyl, 5-chlorothienyl, pyridyland the like.

The heteroarylalkyl at R¹ and R⁵ is a 5 or 6-membered heteroaryl ringsubstituted with 1 or 2 hetero atoms selected from nitrogen atom, sulfuratom and oxygen atom (as defined above), which is substituted with alkylhaving 1 to 4 carbon atoms. Examples thereof include 2-thienylmethyl,2-(2-thienyl)ethyl, 3-(2-thienyl)propyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl and the like.

The cycloalkyl at R¹ and R⁵ is a cycloalkyl having 3 to 6 carbon atoms,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The alkyl at R², R^(2a), R³, R^(3a), R^(4a), R⁶ and R⁷ is a linear orbranched chain alkyl having 1 to 4 carbon atoms, and is exemplified bymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike, preferably methyl.

The halogen at R², R³, R⁶ and R⁷ is fluorine, chlorine, bromine oriodine.

The alkoxy at R², R³, R⁶ and R⁷ is a linear or branched chain alkoxyhaving 1 to 4 carbon atoms, and is exemplified by methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy and the like.

The optionally substituted amino at R², R³, R⁶ and R⁷ may be mono ordi-substituted with a substituent selected from alkyl having 1 to 4carbon atoms (as defined above), acyl having 1 to 4 carbon atoms(formyl, acetyl, propionyl and the like) and benzoyl. Examples thereofinclude amino, methylamino, dimethylamino, ethylamino, diethylamino,formylamino, acetylamino, propionylamino and benzoylamino.

The alkyl, halogen and optionally substituted amino at R⁴ and R⁸ are asdefined for alkyl, halogen and optionally substituted amino at R², R³,R⁶ and R⁷.

The alkyl of optionally substituted alkyl at R⁵ is a linear or branchedchain alkyl having 1 to 6 carbon atoms, and is exemplified by methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl and the like. Examples of the substituentinclude halogen (fluorine, chlorine, bromine, iodine), alkoxycarbonylwherein the alkoxy moiety has 1 to 4 carbon atoms (C1–C4 alkoxy moietyis as defined above) and carboxyl group, and specific examples thereofinclude fluoromethyl, chloromethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,2-(methoxycarbonyl)ethyl, carboxymethyl, 2-carboxyethyl and the like.

The hydroxyalkyl at R⁵ is a linear or branched chain alkyl having 1 to 4carbon atoms (as defined above), which is substituted with hydroxylgroup. Examples thereof include hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl and the like, preferably 2-hydroxyethyl.

The aminoalkyl at R⁵ is a linear or branched chain alkyl having 1 to 4carbon atoms (as defined above), which is substituted with amino. Theamino may be substituted with a substituent selected from alkyl having 1to 4 carbon atoms (as defined above), acyl having 1 to 4 carbon atoms(as defined above) and benzoyl. Examples thereof include aminomethyl,2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl,diethylaminomethyl, dipropylaminomethyl, dibutylaminomethyl,2-dimethylaminoethyl, formylaminomethyl, 2-formylaminoethyl,acetylaminomethyl, 2-acetylaminoethyl, benzoylaminomethyl,2-benzoylaminoethyl and the like.

The alkyl at W and W¹ is a linear or branched chain alkyl having 1 to 4carbon atoms, and is exemplified by methyl, ethyl, propyl, isopropyl,butyl and the like, preferably methyl or ethyl.

The hydroxyalkyl at W is an alkyl having 1 to 4 carbon atoms (as definedabove) which is substituted with hydroxyl group, and is exemplified byhydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and thelike.

The acyloxyalkyl at W is a C1–C4 alkyl (as defined above) substitutedwith acyloxy having 1 to 4 carbon atoms (formyloxy, acetyloxy,propionyloxy, butyryloxy and the like). Examples thereof includeformyloxymethyl, 2-formyloxyethyl, acetyloxymethyl, 2-acetyloxyethyl,3-acetyloxypropyl, 4-acetyloxybutyl, propionyloxymethyl and the like,preferably 2-acetyloxyethyl.

The aminoalkyl at W is a C1–C4 alkyl (as defined above) substituted withamino. Examples thereof include aminomethyl, aminoethyl,dimethylaminomethyl, diethylaminomethyl and the like.

The hydroxycarbonylalkyl at W and W¹ is C1–C4 alkyl (as defined above)substituted with hydroxycarbonyl. Examples thereof includehydroxycarbonylmethyl, 2-hydroxycarbonylethyl, 3-hydroxycarbonylpropyl,4-hydroxycarbonylbutyl and the like, preferably hydroxycarbonylmethyland 3-hydroxycarbonylpropyl.

The alkoxycarbonylalkyl at W, W¹ is a C1–C4 alkyl (as defined above)substituted with alkoxycarbonyl, wherein the alkoxy moiety has 1 to 4carbon atoms (as defined above). Examples thereof includemethoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl,methoxycarbonylbutyl, ethoxycarbonylmethyl, propoxycarbonylmethyl,isopropoxycarbonylmethyl, butoxycarbonylmethyl and the like, preferablyethoxycarbonylmethyl.

The halogen at X and X¹ is fluorine, chlorine, bromine or iodine,preferably chlorine or bromine

The alkyl at X is a linear or branched chain alkyl having 1 to 6 carbonatoms, and is exemplified by methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like,preferably alkyl having 1 to 3 carbon atoms, particularly preferablymethyl.

The alkoxy at X is a linear or branched chain alkoxy having 1 to 6carbon atoms, and is exemplified by methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, hexyloxy and the like, particularly preferably alkoxyhaving 1 to 3 carbon atoms.

The alkenyl at X is a linear or branched chain alkenyl having 2 to 4carbon atoms, and is exemplified by ethenyl, 1-propenyl, 1-butenyl andthe like, particularly preferably ethenyl.

The haloalkyl at X is a linear or branched chain haloalkyl having 1 to 4carbon atoms, and is exemplified by fluoromethyl, chloromethyl,bromomethyl, trifluoromethyl, 2-fluoroethyl, 2-chloromethyl,2,2,2-trifluoroethyl and the like, particularly preferablytrifluoromethyl.

The alkoxycarbonyl at X and X¹ is an alkoxycarbonyl, wherein the alkoxymoiety has 1 to 4 carbon atoms (as defined above). Examples thereofinclude methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like.

The alkynyl at X and X¹ is a linear or branched chain alkynyl having 1to 4 carbon atoms, and is exemplified by ethynyl, 1-propynyl, 1-butynyland the like, particularly preferably ethynyl.

The halogen at X′ is fluorine, chlorine, bromine or iodine, preferablychlorine.

The alkyl at Y is a linear or branched chain alkyl having 1 to 6 carbonatoms, and is exemplified by methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,neohexyl and the like, particularly preferably alkyl having 4 to 6carbon atoms.

The hydroxyalkyl at Y is a linear or branched chain C1–C4 alkyl (asdefined above) substituted with hydroxyl group. Examples thereof includehydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and thelike.

The hydroxycarbonylalkyl at Y is C1–C4 alkyl (as defined above)substituted with hydroxycarbonyl. Examples thereof includehydroxycarbonylmethyl, 2-hydroxycarbonylethyl, 3-hydroxycarbonylpropyl,4-hydroxycarbonylbutyl and the like.

The optionally substituted aminoalkyl at Y is C1–C4 alkyl (as definedabove) substituted with amino, wherein the amino may be mono ordi-substituted with alkyl having 1 to 4 carbon atoms (as defined above),acyl having 1 to 4 carbon atoms (as defined above) and benzoyl and thelike. Examples thereof include aminomethyl, 2-aminoethyl,dimethylaminomethyl, 2-diethylaminomethyl, formylaminomethyl,acetylaminomethyl, 2-formylaminoethyl, 2-acetylaminoethyl,benzoylaminomethyl and the like. The said amino may form cyclic amine,which may have one or two atoms from oxygen atom, sulfur atom andnitrogen atom in the ring. Examples thereof include pyrrolidine,optionally substituted piperidine, homopiperidine, optionallysubstituted piperazine, optionally substituted homopiperazine,morpholine and thiomorpholine and the like. Specific examples thereofinclude piperidinomethyl, 2-piperidinoethyl, morpholinomethyl,2-morpholinoethyl, thiomorpholinomethyl, piperazinomethyl,(4-morpholinopiperidin-1-yl)methyl and the like.

The alkoxy at Y, Y¹ and Y² is a linear or branched chain alkoxy having 1to 6 carbon atoms, and is exemplified by methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, hexyloxy, isohexyloxy, neohexyloxy and the like,preferably alkoxy having 4 to 6 carbon atoms.

The haloalkoxy at Y and Y¹ is a C1–C4 alkoxy (as defined above)substituted with halogen (as defined above). Examples thereof includefluoromethoxy, chloromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy andthe like, preferably 2,2,2-trifluoroethoxy.

The aryloxy at Y and Y¹ is phenyloxy, naphthyloxy and the like,preferably phenyloxy.

The cycloalkyloxy at Y and Y¹ is a cycloalkyloxy having 3 to 6 carbonatoms, and is exemplified by cyclopentyloxy, cyclohexyloxy and the like,preferably cyclohexyloxy.

The hydroxyalkoxy at Y and Y¹ is a linear or branched chain C3–C6 alkoxysubstituted with hydroxy. Examples thereof include 3-hydroxypropoxy,1-methyl-1-hydroxyethoxy, 4-hydroxybutoxy, 5-hydroxypentyloxy and6-hydroxyhexyloxy.

The hydroxycarbonylalkoxy at Y is a linear or branched chain C1–C4alkoxy substituted with hydroxycarbonyl. Examples thereof includehydroxycarbonylmethoxy, 2-hydroxycarbonylethoxy,3-hydroxycarbonylpropoxy and 4-hydroxycarbonylbutoxy.

The optionally substituted aminoalkoxy at Y, Y¹ and Y² is a linear orbranched chain C1–C6 alkoxy (as defined above) substituted with amino.The said amino may have a substituent such as alkyl having 1 to 4 carbonatoms (as defined above), acyl having 1 to 4 carbon atoms (as definedabove) and benzoyl. The said amino may form cyclic amine which may haveone or two atoms from oxygen atom, sulfur atom and nitrogen atom in thering. Examples thereof include pyrrolidine, optionally substitutedpiperidine, homopiperidine, optionally substituted piperazine,optionally substituted homopiperazine, morpholine and thiomorpholine andthe like. Examples thereof include aminomethoxy, aminoethoxy,aminopropoxy, methylaminomethoxy, dimethylaminomethoxy,2-dimethylaminoethoxy, formylaminomethoxy, acetylaminomethoxy,propionylaminomethoxy, benzoylaminomethoxy, morpholinomethoxy,2-morpholinoethoxy, 3-morpholinopropoxy,2,2-dimethyl-3-morpholinopropoxy, 4-morpholinobutoxy,5-morpholinopentyloxy, 6-morpholinohexyloxy, thiomorpholinomethoxy,2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy,2,2-dimethyl-3-thiomorpholinopropoxy, 4-thiomorpholinobutoxy,5-thiomorpholinopentyloxy, 6-thiomorpholinohexyloxy, piperidinomethoxy,2-piperidinoethoxy, 3-piperidinopropoxy,2,2-dimethyl-3-piperidinopropoxy, 4-piperidinobutoxy,5-piperidinopentyloxy, 6-piperidinohexyloxy, piperazinomethoxy,2-piperazinoethoxy, 3-piperazinopropoxy,2,2-dimethyl-3-piperazinopropoxy, 4-piperazinobutoxy,5-piperazinopentyloxy, 6-piperazinohexyloxy, 2-pyrrolidinoethoxy,3-pyrrolidinopropoxy and the like. Of these, 2-dimethylaminoethoxy,4-morpholinobutoxy, 3-morpholinopropoxy, 2-morpholinoethoxy,morpholinomethoxy and 2,2-dimethyl-3-morpholinopropoxy are preferable.

The alkylthio at Y is that wherein the alkyl moiety has 1 to 6 carbonatoms, and is exemplified by methylthio, ethylthio, propylthio,n-butylthio, pentylthio, neopentylthio, hexylthio and the like.

The hydroxyalkylthio at Y is that wherein the alkyl moiety has 1 to 6carbon atoms. Examples thereof include hydroxymethylthio,2-hydroxyethylthio, 3-hydroxypropylthio, 4-hydroxybutylthio,5-hydroxypentylthio and 6-hydroxyhexylthio.

The hydroxycarbonylalkylthio at Y is that wherein the alkyl moiety has 1to 4 carbon atoms. Examples thereof include hydroxycarbonylmethylthio,2-hydroxycarbonylethylthio, 3-hydroxycarbonylpropylthio and4-hydroxycarbonylbutylthio.

The optionally substituted aminoalkylthio at Y, Y¹, Y² is that whereinthe alkyl moiety has a linear or branched chain alkyl having 1 to 6carbon atoms (as defined above). The said amino is optionallysubstituted with alkyl having 1 to 4 carbon atoms (as defined above),acyl having 1 to 4 carbon atoms (as defined above) or benzoyl as asubstituent. The said amino may form cyclic amine which may have one ortwo atoms from oxygen atom, sulfur atom and nitrogen atom in the ring.Examples thereof include pyrrolidine, optionally substituted piperidine,homopiperidine, optionally substituted piperazine, optionallysubstituted homopiperazine, morpholine and thiomorpholine and the like.Specific examples thereof include aminomethylthio, 2-aminoethylthio,3-aminopropylthio, 4-aminobutylthio, dimethylaminomethylthio,diethylaminomethylthio, 2-dimethylaminoethylthio,dimethylaminoethylthio, 3-dimethylaminopropylthio,4-dimethylaminobutylthio, formylaminomethylthio, 2-formylaminoethylthio,acetylaminomethylthio, 2-acetylaminoethylthio, benzoylaminomethylthio,2-benzoylaminoethylthio, morpholinomethylthio, 2-morpholinoethylthio,3-morpholinopropylthio, 4-morpholinobutylthio, 5-morpholinopentylthio,6-morpholinohexylthio, thiomorpholinomethylthio,2-thiomorpholinoethylthio, 3-thiomorpholinopropylthio,4-thiomorpholinobutylthio, 5-thiomorpholinopentylthio,6-thiomorpholinohexylthio, piperidinomethylthio, 2-piperidinoethylthio,3-piperidinopropylthio, 4-piperidinobutylthio, 5-piperidinopentylthio,6-piperidinohexylthio, piperazinomethylthio, 2-piperazinoethylthio,3-piperazinopropylthio, 4-piperazinobutylthio, 5-piperazinopentylthio,6-piperazinohexylthio, 2-pyrrolidinoethylthio and3-pyrrolidinopropylthio.

The alkyl at Z² and Z³ is an alkyl having 1 to 4 carbon atoms (asdefined above). Examples thereof include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl and the like, preferably ethyl.

The hydroxyalkyl at Z² and Z³ is a C1–C4 alkyl (as defined above)substituted with hydroxyl group. Examples thereof include hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like, preferably2-hydroxyethyl.

The aminoalkyl at Z² and Z³ is a C1–C4 alkyl (as defined above)substituted with amino. The amino may be substituted with alkyl having 1to 4 carbon atoms (as defined above), acyl having 1 to 4 carbon atoms(as defined above) or benzoyl. Examples thereof include aminomethyl,aminoethyl, dimethylaminomethyl, diethylaminomethyl, formylaminomethyl,2-formylaminoethyl, acetylaminomethyl, 2-acetylaminoethyl,benzoylaminomethyl and the like.

The group at Z², Z³, Z^(2a) and Z^(3a) that forms, together with theadjacent nitrogen atom, cyclic amine which may have one or two atomsfrom oxygen atom, sulfur atom and nitrogen atom in the ring is cyclicamine selected from pyrrolidine, optionally substituted piperidine,homopiperidine, optionally substituted piperazine, optionallysubstituted homopiperazine, morpholine and thiomorpholine.

The substituent of the aforementioned optionally substituted gotpiperidine is exemplified by hydroxy; carboxy; alkoxycarbonyl whereinthe alkoxy moiety has 1 to 4 carbon atoms (as defined above);hydroxyalkyl having 1 to 4 carbon atoms (as defined above); alkoxyalkoxywherein the alkoxy moiety has 1 to 4 carbon atoms (methoxymethoxy,ethoxymethoxy, propoxymethoxy, butoxymethoxy, 2-methoxyethoxy,3-methoxypropoxy, 4-methoxybutoxy and the like); carboxyalkylcarbonyloxywherein the alkyl moiety has 1 to 4 carbon atoms(carboxymethylcarbonyloxy, 2-carboxyethylcarbonyloxy and the like);acyloxy having 1 to 4 carbon atoms (as defined above); benzoyloxy;phenyl; alkylenedioxy having 1 to 4 carbon atoms (methylenedioxy,ethylenedioxy and the like); oxo; amino optionally mono ordi-substituted with alkyl having 1 to 4 carbon atoms (as defined above),alkoxyalkyl wherein the alkoxy moiety and alkyl moiety each have 1 to 4carbon atoms (methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyland the like) or hydroxyalkyl having 1 to 4 carbon atoms (as definedabove); cyclic amine selected from piperidine optionally having asubstituent (hydroxy, alkoxy having 1 to 4 carbon atoms, oxo and thelike), morpholine, thiomorpholine, piperazine optionally having asubstituent (alkyl having 1 to 4 carbon atoms, acyl having 1 to 4 carbonatoms and the like) and the like (the said cyclic amine may be N-oxide);morpholinomethyl and the like. Examples thereof include piperidin-1-yl,4-hydroxypiperidin-1-yl, 4-carboxypiperidin-1-yl,4-methoxycarbonylpiperidin-1-yl, 4-ethoxycarbonylpiperidin-1-yl,4-((2-carboxyethyl)carbonyloxy)piperidin-1-yl,4-benzoyloxypiperidin-1-yl, 4-piperidinopiperidin-1-yl,4-morpholinopiperidin-1-yl, 4-thiomorpholinopiperidin-1-yl,4-(N-oxidomorpholino)piperidin-1-yl, 4,4-ethylenedioxypiperidin-1-yl,4-oxopiperidin-1-yl, 4-aminopiperidin-1-yl,4-dimethylaminopiperidin-1-yl,4-(N-(2-hydroxyethyl)amino)piperidin-1-yl,4-(N,N-bis(2-hydroxyethyl)amino)piperidin-1-yl,4-(N-(2-hydroxyethyl)-N-methylamino)piperidin-1-yl,4-(4-methylpiperazin-1-yl)piperidin-1-yl,4-(N-(2-hydroxyethyl)amino)piperidin-1-yl,4-(piperazin-1-yl)piperidin-1-yl,4-(4-(4-acetylpiperazin-1-yl)piperidine)-1-yl, 4-phenylpiperidin-1-yl,4-(N-(2-methoxyethyl)amino)piperidin-1-yl,4-(N-(2-methoxyethyl)-N-methylamino)piperidin-1-yl,4-(N,N-bis(2-methoxyethyl)amino)piperidin-1-yl,4-methoxymethoxypiperidin-1-yl, 4-(2-methoxyethyl)oxypiperidin-lyl,4-(2-hydroxyethyl)piperidin-1-yl, 4-(4-hydroxypiperidin-1-yl)piperidin-1-yl, 4-(4-morpholinomethyl)piperidin-1-yl,4-(4-methoxypiperidin-1-yl)piperidin-1-yl,4-(4-oxopiperidin-1-yl)piperidin-1-yl and the like.

The substituent of the aforementioned optionally substituted piperazineis exemplified by alkyl having 1 to 4 carbon atoms (as defined above);carboxyalkyl wherein the alkyl moiety has 1 to 4 carbon atoms(carboxylmethyl, carboxyethyl and the like); hydroxyalkyl having 1 to 4carbon atoms (as defined above); alkoxyalkyl wherein the alkyl moietyand alkoxy moiety have 1 to 4 carbon atoms (as defined above);hydroxyalkoxyalkyl wherein the alkoxy moiety and alkyl moiety each have1 to 4 carbon atoms (hydroxymethoxymethyl, hydroxyethoxyethyl and thelike); carboxy; alkoxycarbonyl wherein the alkoxy moiety has 1 to 4carbon atoms (as defined above); alkoxycarbonylalkyl wherein the alkoxymoiety and alkyl moiety each have 1 to 4 carbon atoms (as definedabove); acyl having 1 to 4 carbon atoms (as defined above); acyloxyalkylwherein the acyl moiety and alkyl moiety have 1 to 4 carbon atoms (asdefined above); optionally substituted aminoalkyl having 1 to 4 carbonatoms (as defined above); carboxyalkylcarbonyloxy wherein the alkylmoiety has 1 to 4 carbon atoms (carboxymethylcarbonyloxy,(2-carboxyethyl)carbonyloxy and the like); heteroaralkyl (C1–C4 alkylsubstituted with heteroaryl such as pyridyl, thienyl, furyl and thelike); phenyl substituted with a substituent selected from halogen (asdefined above), alkyl having 1 to 4 carbon atoms (as defined above) andalkoxy having 1 to 4 carbon atoms (as defined above);3,4,5,6-tetrahydro-2H-pyran-4-yl; 3,4,5,6-tetrahydro-2H-thiopyran-4-yl;5-methylisoxazole-4-ylcarbonyl; 2-cyano-3-hydroxyisocrotonoyl and thelike. Examples thereof include piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-hydroxymethylpiperazin-1-yl,4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl,4-(tert-butoxycarbonyl)piperazin-1-yl, 4-(ethoxycarbonylmethyl)piperazin-1-yl, 4-(2-ethoxycarbonylethyl)piperazin-1-yl,4-(3-methoxycarbonylpropyl)piperazin-1-yl,4-(carboxymethyl)piperazin-1-yl, 4-(2-carboxyethyl)piperazin-1-yl,4-(3-carboxypropyl)piperazin-1-yl,4-((2-carboxyethyl)carbonyloxy)piperazin-1-yl,4-(5-methylisoxazole-4-ylcarbonyl)piperazin-1-yl,4-(2-cyano-3-hydroxyisocrotonoyl)piperazin-1-yl,4-(dimethylaminomethyl)piperazin-1-yl,4-(2-dimethylaminoethyl)piperazin-1-yl,3,5-dimethyl-4-ethoxycarbonylmethylpiperazin-1-yl,3,5-dimethyl-4-carboxymethylpiperazin-1-yl,4-(3-(3-pyridyl)propyl)piperazin-1-yl,4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl,4-(2-acetyloxyethyl)piperazin-1-yl,4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl,4-(3,4,5,6-tetrahydro-2H-thiopyran-4-yl)piperazin-1-yl,4-(4-chlorophenyl)piperazin-1-yl, 4-(4-fluorophenyl)piperazin-1-yl,4-(4-methylphenyl)piperazin-1-yl, 4-(4-methoxyphenyl)piperazin-1-yl,4-methoxymethylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,4-(3-methoxypropyl)piperazin-1-yl and the like.

The above-mentioned optionally substituted homopiperazine may besubstituted with alkyl having 1 to 4 carbon atoms (as defined above) orhydroxyalkyl having 1 to 4 carbon atoms (as defined above). Examplesthereof include homopiperazine, 4-(hydroxymethyl)homopiperazin-1-yl,4-(2-hydroxyethyl)homopiperazin-1-yl, 4-methylhomopiperazin-1-yl and thelike.

The optionally substituted saturated heterocycle at Het which contains ahetero atom selected from oxygen atom and nitrogen atom is a 5 or6-membered ring. The substituent of the said heterocycle is exemplifiedby alkyl having 1 to 4 carbon atoms (as defined above), arylalkyl (asdefined above) and the like. Examples thereof include piperidin-4-yl,1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-benzylpiperidin-4-yl,pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, 1-ethylpyrrolidin-3-yl,1-benzylpyrrolidin-3-yl, 3,4,5,6-tetrahydro-2H-pyran-4-yl,2,3,4,5-tetrahydrofuran-3-yl and the like.

The pharmaceutically acceptable salt of the compound of the presentinvention is exemplified by salts with inorganic acid such ashydrochloride, hydrobromate, sulfate, phosphate, nitrate and the like,salts with organic acid such as acetate, propionate, succinate, maleate,fumarate, benzoate, citrate, malate, methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like, metal salts such as sodium salt,potassium salt, calcium salt, aluminum salt, magnesium salt and the likewhen carboxyl group is contained, salts with amine such as triethylamineand the like, and salts with dibasic amino acid such as lysine and thelike. In addition, the compound of the present invention encompasseshydrate (1 hydrate, ½ hydrate, ¾ hydrate, ¼ hydrate and the like),solvates and the like. The compound of the present invention furtherencompasses N-oxide compound.

When the compound of the present invention has a geometric isomer, thepresent invention encompasses cis compound, trans compound and mixturesthereof. When the present invention contains one or more asymmetriccenters in a molecule, various optical isomers exist. The presentinvention also encompasses optical isomers, racemates, diastereomers andmixtures thereof.

The compound of the present invention can be produced by the followingmethods.

Method 1: The compound (I) of the present invention can be produced bythe following method.

wherein each symbol is as defined above.

The compound (II) and compound (III) are condensed by the followingthree methods.

(1) The compound (II) is converted to acid halide by a conventionalmethod using a halogenating agent such as thionyl chloride and the like.The acid halide is condensed with compound (III) in a suitable solvent(dichloromethane, dichloroethane, chloroform and the like) in thepresence of a base (triethylamine, pyridine, sodium methoxide, sodiumethoxide, sodium hydroxide, potassium hydroxide, sodium acetate and thelike) at a temperature of from −20° C. to the refluxing temperature of asolvent for 30 min to 12 h to give compound (I). In this reaction, thebase to be used can be used as a solvent.

(2) The compound (II) is condensed with compound (III) as necessary in asuitable solvent (dimethylformamide, dimethyl sulfoxide, methanol,ethanol, isopropyl alcohol, butanol and the like) in the presence of acondensing agent (1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole andthe like) or condensed with compound (III) in a suitable solvent(dimethylformamide, dimethyl sulfoxide and the like) in the presence ofphosphoric acid ester such as diethyl cyanophosphate and the like andbase (triethylamine, pyridine and the like) to give compound (I). Thereaction temperature is generally from 0° C. to 100° C. and the reactiontime is generally from 30 min to 24 h. The reaction using a condensingagent can be carried out in the presence of 1-hydroxybenztriazole andthe like as necessary.

(3) The compound (II) is converted to lower alcohol ester (methyl ester,ethyl ester and the like) or carbonate (mixed acid anhydride with methylchlorocarbonate, ethyl chlorocarbonate and the like), and condensed withcompound (III) in a suitable solvent (methanol, ethanol, isopropylalcohol, butanol, ethylene glycol, tetrahydrofuran, toluene,nitrobenzene or a mixed solvent thereof and the like) or without solventin the presence of a base (triethylamine, pyridine, sodium methoxide,sodium ethoxide, sodium hydroxide, potassium hydroxide and the like) ata temperature of from roan temperature to the refluxing temperature of asolvent for 1–24 h to give compound (I).

When W of compound (III) is hydrogen in this reaction, a protectinggroup generally used in the organic synthetic chemistry, such astert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group,benzyloxycarbonyl group and the like, can be also used for the reaction.

Method 2: A compound (I) wherein W is hydroxyalkyl, alkyl, acyloxyalkyl,aminoalkyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl [compound (I-2)]can be produced by the following method.

wherein W^(a) is alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl,hydroxycarbonylalkyl or alkoxycarbonylalkyl, Hal is halogen such aschlorine, bromine, iodine and the like, and other symbols are as definedabove.

The compound (I-2) can be obtained by reacting compound (I-1) withcompound (IV) in a suitable solvent (dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, hexane, tetrahydrofuran, diethylether, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and thelike) in the presence of a base (sodium hydride, sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, sodiummethoxide, sodium ethoxide, triethylamine and the like) at a temperatureof from −20° C. to 100° C. for 30 min to 24 h.

Method 3: A compound (I) wherein R¹ is arylalkyl, heteroarylalkyl orcycloalkyl [compound (I-4)] can be produced by the following method.

wherein R^(1b) is arylalkyl (same as arylalkyl at R¹), heteroarylalkyl(same as heteroarylalkyl at R¹) or cycloalkyl (same as cycloalkyl at R¹)and other symbols are as defined above.

The compound (I-3) is reacted with compound (V) in a suitable solvent(dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene,tetrahydrofuran, diethyl ether, methanol, ethanol, isopropyl alcohol,tert-butyl alcohol and the like) in the presence of a base (sodiumhydride, sodium hydroxide, potassium hydroxide, potassium carbonate,sodium carbonate, sodium methoxide, sodium ethoxide, triethylamine andthe like) at a temperature of from −20° C. to 100° C. for 30 min to 24 hto give compound (I-4).

Method 4: A compound (I) wherein Y is optionally substituted alkoxy,aryloxy, cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionallysubstituted aminoalkoxy, alkylthio, hydroxyalkylthio,hydroxycarbonylalkylthio, optionally substituted aminoalkylthio or agroup N(Z²) (Z³) [compound (I-6)] can be produced by the followingmethod.

wherein Y^(a) is optionally substituted alkoxy, aryloxy, cycloalkyloxy,hydroxyalkoxy, hydroxycarbonylalkoxy, optionally substitutedaminoalkoxy, alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio,optionally substituted aminoalkylthio or a group N(Z²) (Z³) (wherein Z²and Z³ are the same or different and each is hydrogen, alkyl,hydroxyalkyl or aminoalkyl, or form cyclic amine together with theadjacent nitrogen atom) and other symbols are as defined above.

The compound (I-5) can be obtained by reacting and treating compound(II) and compound (III-a) in the same manner as in Method 1.

The compound (I-5) is reacted with H—Y^(a) in a suitable solvent(dimethyl sulfoxide, dimethylformamide, dichloromethane, chloroform andthe like) in the presence of a base (triethylamine, pyridine and thelike) at a temperature of from 0° C. to the refluxing temperature of thesolvent to be used for 30 min to 24 h to give compound (I-6). It ispossible to use an excess H—Y^(a) instead of the base for the reaction.

Method 5: A compound (I) wherein X is alkenyl or alkynyl [compound(I-8)]can be also produced by the following method.

wherein P¹ is a protecting group of triple bond such as trimethylsilyland the like, X^(a) is alkynyl such as acetylene and the like, M ismetal such as tin and the like or boron, X^(b) is alkenyl such as vinyland the like, n is an integer of 3 or 4, X^(c) is alkynyl such asacetylene and the like or alkenyl such as vinyl and the like, and othersymbols are as defined above.

The compound (I-7) is subjected to Sonogashira coupling reaction in thepresence of a palladium catalyst (bis(triphenylphosphine)palladiumdichloride or tetrakis(triphenylphosphine)palladium and the like) usingalkyne such as trimethylsilylacetylene and the like, Suzuki couplingreaction using alkenylborane (vinylborane and the like) or Stillecoupling reaction using alkenyltin (tetravinyltin and the like) to givecompound (I-8). In the Sonogashira coupling reaction, compound (I-7) andcompound P¹—X^(a) can be reacted in the presence of atetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium dichloride and cuprous iodide as acatalyst, wherein the solvent to be used is exemplified bytriethylamine, diethylamine, piperidine and the like. The reactiontemperature is generally from room temperature to the refluxingtemperature of the solvent, and the reaction time is generally 1–24 h.After the Sonogashira coupling reaction, by reacting under moderatealkaline conditions using potassium carbonate, sodium hydroxide and thelike in an alcohol solvent such as methanol and the like at atemperature of from room temperature to the refluxing temperature of asolvent for 1–24 h, a compound (I-8) wherein X^(c) is alkynyl (acetyleneand the like) can be obtained.

In the Stille coupling reaction, compound (I-7) is reacted withalkenyltin (tetravinyltin and the like) usingtetrakis(triphenylphosphine)palladium and the like as a catalyst to givecompound (I-8) wherein X^(c) is alkenyl (vinyl and the like). Thesolvent to be used is benzene, toluene, tetrahydrofuran,dimethylformamide, N-methylpyrrolidone and the like. Where necessary, anadditive such as lithium chloride and the like, or a base such astriethylamine, diisopropylethylamine and the like is used. The reactiontemperature is generally from room temperature to the refluxingtemperature of a solvent, and the reaction time is generally 1–24 h.

Method 6: A compound (I) wherein W is hydrogen [compound (I-1)] can bealso produced by the following method.

wherein each symbol is as defined above.

The compound (VI) and compound (VII) are subjected to Friedel-Craftreaction in a suitable solvent (tetrahydrofuran, diethyl ether, ethyleneglycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylenechloride, chloroform, dichloroethane, acetonitrile, nitromethane, carbondisulfide and the like) or without solvent where necessary in thepresence of an acid catalyst (aluminum chloride, aluminum bromide,titanium tetrachloride and the like) at a temperature of from −20° C. to100° C. for 30 min to 24 h to give compound (VIII). The compound (VIII)is subjected to Schmidt reaction in a suitable solvent (benzene,toluene, xylene and the like, preferably benzene) using a strong acid(sulfuric acid, trifluoroacetic acid and the like) and sodium azide at atemperature of from −20° C. to the refluxing temperature of the solventfor 1–24 h to give compound (I-1).

Method 7: The compound (I-1) can be also produced by the followingmethod.

wherein Lv is hydrogen or arylsulfonyl group such as benzenesulfonyl andthe like, and other symbols are as defined above.

The compound (IX) and compound (X) are reacted in a suitable solvent(water, methanol, ethanol or a mixed solvent thereof and the like) inthe presence of a base (sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, sodium acetate, triethylamine and thelike) at a temperature of from −20° C. to 100° C. for 1–24 h to givecompound (XI). The compound (XI) is subjected to Beckmann rearrangementreaction in a suitable solvent (water, dimethyl sulfoxide,dimethylformamide, benzene, toluene, xylene or a mixed solvent thereofand the like) at a temperature of from room temperature to the refluxingtemperature of a solvent for 1–24 h to give compound (I-1).

Method 8: When the compound of the present invention has a hydroxylgroup, the corresponding ester compound can be obtained by subjectingthe compound to condensation generally used in the field of organicsynthetic chemistry with a carboxylic acid compound, an acid halidecompound or an acid anhydride compound. When the compound of the presentinvention has a carboxyl group, the corresponding ester compound can beobtained by subjecting the compound to condensation generally used inthe field of organic synthetic chemistry with an alcohol compound orphenol compound. Furthermore, when the compound of the present inventionhas an ester group, the corresponding carboxylic acid compound can beobtained by subjecting the compound to hydrolysis by a conventionalmethod with an acid (hydrochloric acid, sulfuric acid and the like) or abase (sodium hydroxide, potassium hydroxide and the like). When thecompound of the present invention has an amino group, the compound canbe N-alkylated or N-acylated by a conventional method in the presence ofa base (triethylamine, pyridine and the like) using an alkyl halide oracyl halide. When the compound of the present invention has a hydroxylgroup, the compound can be converted to carbonyl group or aldehyde groupby oxidation known in the field of organic synthetic chemistry usingchromic acid-sulfuric acid, chromium oxide (VI)-sulfuric acid-acetone(Jones reagent), chromium oxide (VI)-pyridine complex (Collins reagent),dichromate (sodium dichromate, potassium dichromate and thelike)-sulfuric acid, pyridinium chlorochromate (PCC), manganese dioxide,dimethyl sulfoxide-electrophilic activating reagent(dicyclohexylcarbodiimide, acetic anhydride, phosphorus pentaoxide,sulfur trioxide-pyridine complex, anhydrous trifluoroacetic acid, oxalylchloride, halogen), sodium hypochlorite, potassium hypochlorite, sodiumbromite and the like.

Method 9: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with alkyl at the 3-position, withhydrogen or alkyl at the 5-posiiton and with carboxy group at the4-position [compound (II-1)] can be produced by the following method.

wherein R^(a) is hydrogen or alkyl having 1 to 4 carbon atoms, R^(b) andR^(c) are each alkyl having 1 to 4 carbon atoms, and other symbols areas defined above.

The compound (XII) and compound (XIII) are reacted in a suitable solvent(water, methanol, ethanol, isopropyl alcohol, butanol, ethylene glycolor a mixed solvent thereof) at a temperature of from room temperature tothe refluxing temperature of a solvent for 1–24 h to give compound(XIV).

The compound (XIV) is reacted in a suitable solvent (water, methanol,ethanol or a mixed solvent thereof) using an acid (hydrochloric acid,sulfuric acid and the like) or an alkali (sodium hydroxide, potassiumhydroxide and the like) at a temperature of from room temperature to therefluxing temperature of a solvent for 1–12 h to give compound (II-1).

The compound (XII) can be produced according to J. Chem. Soc. PerkinTrans I), p. 1875 (1988).

Method 10: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with hydrogen or an alkyl at the3-position, with carboxyl group at the 4-position, and with amino at the5-position [compound (II-3)] can be produced by the following method.

wherein each symbol is as defined above.

The reaction of compound (XV) and compound (XIII) and hydrolysis ofcompound (XVI) can be conducted under the same reaction condition as inMethod 9.

Method 11: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with alkyl at the 3-position, withcarboxyl group at the 4-position, and with amino at the 5-position[compound (II-2)] can be produced by the following method.

wherein each symbol is as defined above.

The reaction of compound (XVII) and compound (XIII) and hydrolysis ofcompound (XVIII) can be conducted under the same reaction condition asin Method 9.

Method 12: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with hydrogen or alkyl at the3-position, with carboxyl group at the 4-position, and with hydroxylgroup at the 5-position [compound (II-4)] can be produced by thefollowing method.

wherein R^(d) is alkyl having 1 to 4 carbon atoms and other symbols areas defined above.

The reaction of compound (XIX) and compound (XIII) and hydrolysis ofcompound (XX) can be conducted under the same reaction condition as inMethod 9.

Method 13: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with hydrogen or alkyl at the3-position, with alkyl at the 5-position, and with carboxyl group at the4-position [compound (II-5)] can be produced by the following method.

wherein each symbol is as defined above.

The reaction of compound (XXI) and compound (XIII) and hydrolysis ofcompound (XXII) can be conducted under the same reaction condition as inMethod 9.

Method 14: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with hydrogen or alkyl at the3-position, with carboxyl group at the 4-position, and with amino at the5-position [compound (II-2′)] can be produced by the following method.

wherein each symbol is as defined above.

The compound (XXIII) and compound (XIII) are reacted in a suitablesolvent (water, methanol, ethanol, propanol, butanol, ethylene glycol ora mixed solvent thereof) at a temperature of from room temperature tothe refluxing temperature of a solvent for 1–24 h to give compound(XXIV) and the compound (XXIV) is treated by a conventional method withan acid (hydrochloric acid, sulfuric acid and the like) or an alkali(sodium hydroxide, potassium hydroxide and the like) in a suitablesolvent (water, methanol, ethanol or a mixed solvent thereof) to givecompound (II-2′).

Method 15: A compound (II) having substituted amino can be obtained asfollows. The carboxyl group of compound (II-2) is protected with asuitable protecting group and reacted with halogenated alkyl in thepresence of a base (triethylamine, pyridine and the like), or subjectedto reductive N-alkylation with alkylaldehyde in an organic acid(preferably formic acid), followed by deprotection to give a compoundhaving mono or di-substituted amino. The compound (II-2) can be alsoobtained by hydrolysis after the above-mentioned N-alkylation ofcompound (XXIV).

Method 16: A compound (II) having a pyrazole ring wherein Q is nitrogenatom, which ring is substituted with chlorine at the 5-position, withhydrogen or alkyl at the 3-position, and with carboxyl group at the4-position [compound (II-6)] can be produced by the following method.

wherein each symbol is as defined above.

The compound (XXV) is reacted with chlorinating agent (sulfuryl chlorideand the like) in a suitable solvent (toluene, benzene, n-hexane or amixed solvent thereof), at a temperature of from room temperature to therefluxing temperature of a solvent for 1–24 h to give compound (XXVI).The compound (XXVI) is hydrolyzed according to a conventional methodusing an acid (hydrochloric acid, sulfuric acid and the like) or analkali (sodium hydroxide, potassium hydroxide and the like) to givecompound (II-6).

Method 17: A compound (II) wherein R¹ is arylalkyl, heteroarylalkyl orcycloalkyl [compound (II-7)] can be produced by the following method.

wherein Lv′ is a leaving group such as halogen (chlorine, bromine,iodine and the like), methanesulfonyloxy, p-toluenesulfonyloxy and thelike, and other symbols are as defined above.

The compound (XXVII) and compound (XXVIII) are reacted in a suitablesolvent (dimethylformamide, dimethyl sulfoxide, benzene, toluene,xylene, methylene chloride, chloroform and the like) in the presence of,where necessary, a metal catalyst (copper powder, copper chloride,copper sulfate, silver carbonate, silver nitrate and the like) in a base(potassium carbonate, barium carbonate, sodium hydride and the like) ata temperature of from −20° C. to 100° C. for 1–24 h to give compound(XXIX). The compound (XXIX) is hydrolyzed according to a conventionalmethod using an acid (hydrochloric acid, sulfuric acid and the like) oran alkali (sodium hydroxide, potassium hydroxide and the like) to givecompound (II-7).

Method 18: The compound (II-1) can be also produced by the followingmethod.

wherein each symbol is as defined above.

The compound (XXX) is subjected to Vilsmeier reaction using phosphorusoxychloride in the presence of N,N-dimethylformamide orN-methylformanilide at a temperature of from room temperature to 100° C.for 1–24 h to give compound (XXXI). The compound (XXXI) is subjected tooxidation with an oxidizing agent (manganese dioxide, potassiumpermanganate, peroxidate (hydrogen peroxide, m-chloroperbenzoic acidetc.) and the like) in a suitable solvent (water, diethyl ether,tetrahydrofuran, dioxane, acetone, tert-butyl alcohol, methylenechloride, chloroform, hexane, benzene, toluene or a mixed solventthereof) to give compound (II-1). The compound (XXX) can be obtainedaccording to the method described in Bull. Soc. Chim. France, p. 1346,1970.

Method 19: The compound (II-1) can be also produced by the followingmethod.

wherein each symbol is as defined above.

The compound (XXX) and oxalyl chloride are reacted at a temperature offrom room temperature to the refluxing temperature of a solvent for 1–24h to give compound (XXXII). The compound (XXXII) is reacted in anaqueous solution for 1–24 h to give compound (II-1).

Method 20: A compound (II) having a pyrrole ring wherein Q is C—R⁴ whereR⁴ is hydrogen, which ring is substituted with carboxyl group at the3-position, and unsubstituted at the 2- and 4-positions [compound(II-8)] can be produced by the following method.

wherein each symbol is as defined above.

The compound (XXXIII) and compound (XXXIV) are reacted in a suitablesolvent (diethyl ether, dimethyl ether, n-hexane or a mixed solventthereof) at a temperature of from room temperature to the refluxingtemperature of a solvent for 1–24 h to give compound (XXXV). Thecompound (XXXV) is subjected to oxidation with an oxidizing agent(manganese dioxide, potassium permanganate, peroxidate (hydrogenperoxide, m-chloroperbenzoic acid etc.) and the like) in the presence ofa base (sodium hydroxide, potassium hydroxide, triethylamine, pyridineand the like) to give compound (II-8).

The compound (XXXIII) can be also obtained according to the methoddescribed in Synthetic Communications, vol. 13, No. 9, pp. 741–744(1983). The compound (XXXV) can be also obtained according to the methoddescribed in Synthetic Communications, vol. 24, No. 13, p. 1855 (1994).

Method 21: The compound (XXXV) can be also produced by the followingmethod.

wherein each symbol is as defined above.

The compound (XXXVI) is reacted with trifluoromethanesulfonic acid in asuitable solvent (methylene chloride, chloroform, dichloroethane,benzene, toluene, xylene and the like) at a temperature of from roomtemperature to the refluxing temperature of a solvent for 1–24 h to givecompound (XXXV).

Method 22: The compound (XXXVI) can be produced by the following method.

wherein each symbol is as defined above.

The compound (XXXVII) and compound (XXXIV) are reacted in a suitablesolvent (diethyl ether, dimethyl ether, n-hexane or a mixed solventthereof) at a temperature of from room temperature to the refluxingtemperature of a solvent for 1–24 h to give compound (XXXVIII). Thecompound (XXXVIII) is reacted with phosphorus oxychloride usingVilsmeier reaction in the presence of N,N-dimethylformamide or in thepresence of N-methylformanilide at a temperature of from roomtemperature to 100° C. for 1–24 h to give compound (XXXVI).

Method 23: A compound (II) having a pyrrole ring wherein Q is C—R^(e),which ring is substituted with alkyl at both the 2- and 5-positions,carboxyl group at the 3-position, and unsubstituted at the 4-position[compound (II-9)] can be produced by the following method.

wherein R^(h) and R^(i) are each alkyl having 1 to 4 carbon atoms andother symbols are as defined above.

Utilizing the pyrrole synthetic method of Paal-Knorr, compound (XXXVII)and compound (XXXIV) are condensed in N,N-dimethylformamide or withoutsolvent in the presence of an acid catalyst (hydrochloric acid, sulfuricacid and the like) where necessary at a temperature of from 20° C. to100° C. for 1–24 h to give compound (XXXVIII). The formylation ofcompound (XXXVIII) and oxidation of compound (XXXIX) can be conductedunder the same reaction condition as in Method 20.

Method 24: The compound (II-9) can be also produced by the followingmethod.

wherein each symbol is as defined above.

The compound (XL) is subjected to Friedel-Craft reaction in a suitablesolvent (tetrahydrofuran, dioxane, diethyl ether, dichloromethane,dichloroethane, chloroform, ethylene glycol dimethyl ether,acetonitrile, nitromethane, carbon disulfide or a mixture thereof) orwithout solvent in the presence of an acid catalyst (aluminum chloride,aluminum bromide, titanium chloride and the like) at a temperature offrom −20° C. to 100° C. for 30 min to 24 h to give compound (XLI).Utilizing the Haloform reaction, the compound (XLI) is treated with analkali (sodium hydroxide, potassium hydroxide and the like) and ahalogenating agent (bromine, chlorine, sodium (potassium) hypochlorite,sodium (potassium) hypobromite and the like) in a suitable solvent(water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,tetrahydrofuran, dioxane or a mixture thereof and the like) at atemperature of from −20° C. to 100° C. for 30 min to 24 h to givecompound (II-9).

Method 25: A compound (III) wherein W is hydrogen [compound (III-1)] canbe produced by the following method.

wherein each symbol is as defined above.

The compound (XLII) is subjected to reduction generally used in thefield of organic synthetic chemistry, such as a method comprisingtreating with dilute hydrochloric acid or a catalytic amount of ammoniumchloride in a suitable solvent (water, methanol, ethanol, propanol,butanol, ethylene glycol or a mixed solvent thereof and the like) usingiron powder or tin chloride as a catalyst; a method comprising treatingwith a catalytic amount of iron chloride and hydrazine; catalyticreduction by hydrogenation in the presence of a catalyst such as nickel,palladium, platinum and the like; Birch reduction using alkali metalsuch as sodium, lithium and the like in liquid ammonia, and the like togive compound (III-1). The reaction temperature is generally from roomtemperature to the refluxing temperature of a solvent and the reactiontime is generally 1–24 h.

Method 26: The compound (III-1) can be also produced by the followingmethod.

wherein each symbol is as defined above.

Utilizing the Schmidt reaction, compound (XLIII) is treated with sodiumazide and a strong acid (sulfuric acid, trifluoroacetic acid and thelike) in a suitable solvent (water, methanol, ethanol, propanol,butanol, tert-butyl alcohol, ethylene glycol, benzene, toluene orxylene, preferably benzene) at a temperature of from room temperature tothe refluxing temperature of a solvent for 1–24 h, or reacted withtriethylamine and diphenylphosphonyl azide in a suitable solvent(methanol, ethanol, isopropyl alcohol, butanol or tert-butanol,preferably tert-butanol) at a temperature of from room temperature tothe refluxing temperature of a solvent for 1–24 h, followed by treatmentwith an acid (hydrochloric acid, sulfuric acid and the like) to givecompound (III-1).

Method 27: A compound (XLII) wherein X′ is hydrogen, X is halogensubstituted at the 3-position, and Y is alkoxy substituted at the4-position can be produced by the following method.

wherein R is alkyl having 1 to 6 carbon atoms and other symbols are asdefined above.

4-Nitrophenol is reacted with haloalkyl in a suitable solvent (water,dimethyl sulfoxide, dimethylformamide, toluene, methanol, ethanol,tetrahydrofuran or a mixed solvent thereof and the like) in the presenceof a base (sodium hydroxide, sodium hydride, sodium methoxide, sodiumethoxide, butyllithium, butylmagnesium chloride and the like) at atemperature of from −20° C. to the refluxing temperature of a solventfor 1–24 h to give compound (XLIV). The compound (XLIV) is reacted withhalogen (chlorine, bromine and the like) at a temperature of from −20°C. to room temperature for 1–24 h to give compound (XLII-1). Thecompound (XLII-1) can be also obtained by halogenating 4-nitrophenol,followed by alkylation under the above-mentioned reaction conditions.

Method 28: A compound (XLII) wherein X′ is hydrogen, X is cyanosubstituted at the 3-position, and Y is halogen substituted at the4-position can be produced by the following method.

wherein each symbol is as defined above.

The compound (XLV) is treated with a halogenating agent (thionylchloride and the like) to convert to an acid halide, and reacted withaqueous ammonia at a temperature of from −20° C. to room temperature for30 min to 24 h to give compound (XLVI). The compound (XLVI) is reactedwith toluenesulfonic chloride in the mixed solvent ofpyridine-dimethylformamide at a temperature of from room temperature to100° C. for 1–24 h to give compound (XLII-2).

The compound (XLII-2) can be also produced by reacting compound (XLV) inthe presence of a phosphorus pentachloride and toluenesulfonamide at atemperature of from room temperature to 200° C. for 30 min to 12 h andtreating with a base such as pyridine and the like at a temperature offrom 0° C. to 40° C. for 1–24 h.

Method 29: A compound (XLII) wherein Y is alkoxy, hydroxyalkoxy,hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, alkylthio,hydroxyalkylthio, hydroxycarbonylalkylthio, optionally substitutedaminoalkylthio or a group N(Z²)(Z³) can be produced by the followingmethod.

wherein Y^(a) is alkoxy, hydroxyalkoxy, hydroxycarbonylalkoxy,optionally substituted aminoalkoxy, alkylthio, hydroxyalkylthio,hydroxycarbonylalkylthio, optionally substituted aminoalkylthio or agroup N(Z²) (Z³), and other symbols are as defined above.

The compound (XLII-3) is reacted with compound (XLVII) in a suitablesolvent (chloroform, acetonitrile, water, methanol, ethanol,tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide ora mixed solvent thereof and the like) or without solvent in the presenceof a base (sodium hydroxide, sodium methoxide, sodium ethoxide, sodiumhydride, butyllithium and the like) at a temperature of from −20° C. to100° C. for 1–24 h to give compound (XLII-4).

A compound (XLII-4) wherein Y^(a) is hydroxyalkoxy or hydroxyalkylthio,which is obtained by this method, can be converted to compound (XLII-4)wherein Y^(a) is aminoalkoxy or aminoalkylthio by treating its hydroxylgroup with a halogenating agent such as thionyl chloride and the like,methanesulfonyl chloride or p-toluenesulfonyl chloride etc. to give thecorresponding halogenated compound or sulfonyl compound, which is thensubjected to the same reaction and treatment with HN(Z²) (Z³) as in theabove-mentioned method.

Method 30: A compound (XLII) or compound (XLIII) wherein X is cyano canbe produced by the following method.

wherein G is nitro or carboxy and other symbols are as defined above.

The compound (XLVIII) is reacted with a cyanide agent (sodium cyanide,potassium cyanide, cuprous cyanide and the like) in a suitable solvent(water, methanol, ethanol, propanol, ethylene glycol, dimethylsulfoxide, dimethylformamide or a mixed solvent thereof and the like) ata temperature of from room temperature to 100° C. for 1–24 h to givecompound (XLIX). The compound (XLIX) can be also produced by using atetrakis(phenylphosphine)palladium catalyst and a cyanating agent suchas zinc cyanide and the like.

Method 31: A compound (III) wherein W is alkyl, hydroxyalkyl,acyloxyalkyl, aminoalkyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl[compound (III-2)] can be produced by the following method.

wherein each symbol is as defined above.

The compound (III-1) is reacted with compound (IV) in the presence ofsodium acetate without solvent or in a suitable solvent(tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxideand the like) at a temperature of from room temperature to 60° C. for1–24 h to give compound (III-2).

The compound (III-2) can be also obtained by protecting compound (III-1)by a conventional method with tert-butoxycarbonyl and the likeconventionally used generally as an amino-protecting group, reactingwith compound (IV) in the presence of metal sodium, sodium hydride,sodium amide and the like and then deprotecting by a conventionalmethod.

Method 32: The compound (I-c) can be produced according to theabove-mentioned Methods 1–31. The starting compound for the productionof compound (I-c), which is the compound of the formula

wherein each symbol is as defined above, having a pyrazole ring whereinQ is nitrogen atom, and having carboxyl group at the 3- or 5-position,can be produced by the following method.

wherein R^(f) is alkyl having 1 to 4 carbon atoms, R^(g) is hydrogen oralkyl having 1 to 4 carbon atoms, and other symbols are as definedabove.

The reaction of compound (L) and compound (XIII) and hydrolysis ofcompounds (LI-1) and (LI-2) can be conducted under the same reactioncondition as in Method 9.

A compound having a pyrrole ring wherein Q is C—R⁴ where R⁴ is hydrogen,which ring having carboxyl group at the 2-position can be produced bythe following method

wherein each symbol is as defined above.

The oxidation of compound (LII) can be conducted under the same reactioncondition as in Method 20.

The compound of the present invention can be converted to an acidaddition salt by treating the compound with an acid (inorganic acid suchas hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like, or organic acid such as acetic acid, propionicacid, succinic acid, maleic acid, fumaric acid, benzoic acid, citricacid, malic acid, methanesulfonic acid, benzenesulfonic acid and thelike) in, where necessary, a suitable solvent (water, methanol, ethanol,propanol, isopropyl alcohol, diethyl ether, tetrahydrofuran, dioxane andthe like). When the obtained compound has a carboxyl group, the compoundcan be treated with sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, magnesium hydroxide, sodium alcoholateand the like to give the corresponding metal salt, and treated withamine, such as triethylamine and the like, or a dibasic amino acid, suchas lysine and the like, in, where necessary, a suitable solvent to givethe corresponding salt. In addition, when crystal of the compound of thepresent invention is anhydride, it can be treated with water, hydroussolvent or other solvent to give a hydrate (1 hydrate, ½ hydrate, ¾hydrate, ¼ hydrate and the like) or a solvate. Moreover, the compound ofthe present invention can be converted to an N-oxide compound bytreating it with an oxidizing agent, such as hydrogen peroxide,m-chloroperbenzoic acid and the like, according to a conventionalmethod.

The compound of the present invention thus obtained can be isolated andpurified by a method known in the field of organic synthetic chemistry,such as recrystallization, column chromatography and the like. When theobtained product is a racemate, it can be resolved into a desiredoptically active compound by, for example, fractional crystallizationinto a salt with an optically active acid or base, or passing through acolumn packed with an optically active carrier. These can be alsoproduced by using an optically active starting compound and the like.

Because the compound of the present invention and a pharmaceuticallyacceptable salt thereof have been clarified to show a superiorinhibitory effect on the proliferation of activated lymphocytes,particularly inhibitory effect on lymphocyte proliferation dependent onIL-2, IL-4, IL-7, IL-9, IL-13 or IL-15, and inhibit the production ofIL-15 as well as inflammatory cytokines (IL-1, IL-6, IL-12, IL-15,IL-18, TNF-a and the like) derived by IL-15, and also inhibit thephosphorylation of tyrosine kinase represented by JAK1, JAK3 and thelike, which are present in the signal transduction path involved in theproliferation of lymphocytes derived by IL-15, they can be used for theprophylaxis or treatment of various autoimmune diseases. Moreparticularly, the compound of the present invention and apharmaceutically acceptable salt thereof can be used for the treatmentand prophylaxis of the diseases caused by lymphocyte proliferation,particularly autoimmune diseases such as rheumatoid arthritis, systemiclupus erythematosus, nephrotic syndrome lupus, Hashimoto's struma,multiple sclerosis, myasthenia gravis, type I diabetes, type II adultonset type diabetes mellitus, uveitis, nephrotic syndrome,steroid-dependent and steroid resistant nephrosis, pustulosispalmoplantaris, allergic encephalomyelitis, glomerular nephritis and thelike, as well as for infection with pathogenic microorganisms. Moreover,they can be used for the treatment of inflammatory, proliferative andsuperproliferative dermatosis, onset on the skin of immunity-mediateddiseases, such as psoriasis, psoriatic arthritis, atopic eczema (atopicdermatitis), contact dermatitis, eczematous dermatitis, seborrheicdermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysisbullosa, urticaria, vascular edema, angitis, erythema, eosinophilicincrease of skin, acne, alopecia areata, eosinophilic fasciitis andatherosclerosis. The compound of the present invention more specificallyprevents epilation, forms hair germ and/or produces and grows hair, andcan be used for recovery of hair by treating female or male patternalopecia and senile alopecia.

The compound of the present invention is also applicable to respiratorydiseases, such as sarcoidosis, fibroid lung, idiopathic interstitialpneumonia and reversible obstructive airway diseases, and to thetreatment of symptoms such as asthma including bronchial asthma,infantile asthma, allergic asthma, intrinsic asthma, extrinsic asthmaand dust asthma, particularly chronic and intractable asthma (e.g., lateasthma and airway irritation), bronchitis and the like. The compound ofthe present invention can be used for the treatment of liver disordersrelated to ischemia. It is also effective for particular eye diseasessuch as conjunctivitis, keratoconjunctivitis, keratitis, vernalconjunctivitis, Behcet disease-related uveitis, herpetic keratitis,keratoconus, corneal epithelial degeneration, keratoleukoma, ocularpemphigus, Mooren's ulcer, scleritis, Graves, disease, severeintraocular inflammation and the like.

The compound of the present invention can be used for the prophylaxis ortreatment of mucosal or vascular inflammation [e.g., leukotrieneB4-mediated disease, gastric ulcer, vascular injury caused by thrombosisand ischemic disease, ischemic intestinal disease, inflammatory boweldisease (e.g., Crohn's disease and ulcerative colitis), necrotizingenterocolitis] and bowel injury relating to thermal burn. Thecomposition of the present invention can be also used for theprophylaxis or treatment of renal diseases such as interstitialnephritis, Goodpasture's syndrome, hemolytic uremic syndrome anddiabetic nephropathy; nervous disease selected from multiple myositis,Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrinediseases such as hyperthyroidism and Basedow's disease; hematic diseasessuch as pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,granulocytopenia and anerythroplasia; diseases of bone such asosteoporosis; respiratory diseases such as sarcoidosis, fibroid lung andidiopathic interstitial pneumonia; dermatosis such as dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity andskin T-cell lymphoma; circulatory diseases such as arteriosclerosis,aortitis, polyarteritis nodosa and myocardiopathy; collagen diseasessuch as scleroderma, Wegener's granulomatosis and Sjögren's syndrome;adiposis; eosinophilic fasciitis; periodontal disease; nephroticsyndrome; hemolytic uremic syndrome; and muscular dystrophy.

The compound of the present invention is suitable for the prophylaxis ortreatment of bowel inflammation/allergy, such as Coeliac disease,proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's diseaseand ulcerative colitis; and allergic diseases related to food, whichshows symptoms directly unrelated to the gastrointestinal tract, such asmigraine, rhinitis and eczema. Due to the liver regeneration activityand/or hepatocyte hypertrophy and hyperplasia promoting activity, thecompound of the present invention can be used for the prophylaxis ortreatment of liver diseases such as immunogenic diseases (e.g., chronicautoimmune liver diseases including autoimmune hepatitis, primarybiliary cirrhosis and sclerosing cholangitis), partial hepaticresection, acute liver necrosis (necrosis due to toxin, viral hepatitis,shock or oxygen deficiency), viral hepatitis type B, non-A non-B viralhepatitis and cirrhosis.

Where the case demands, the compound of the present invention can bealso used for the prophylaxis or treatment of malignant rheumatoidarthritis, amyloidosis, fulminant hepatitis, Shy-Drager syndrome,pustular psoriasis, Behcet's disease, systemic lupus erythematodes,endocrine ophthalmopathy, progressive systemic sclerosis, mixedconnective tissue disease, aortitis syndrome, Wegener's granulomatosis,active chronic hepatitis, Evans syndrome, pollinosis, idiopathichypoparathyroidism, Addison's disease (autoimmune adrenalitis),autoimmune orchitis, autoimmune oophoritis, cold hemagglutinin disease,paroxysmal cold hemoglobinuria, pernicious anemia, adult T cellsleukemia, autoimmune atrophic gastritis, lupoid hepatitis,tubulointerstitial nephritis, membranous nephropathy, amyotrophiclateral sclerosis, rheumatic fever, postmyocardial infarction syndromeand sympathetic ophthalmia.

Where the case demands, the compound of the present invention or apharmaceutically acceptable salt thereof can be used along with otherantirheumatic drug (gold compound, penicillamine, bucillamine,lobenzarit, actarit, salazosulfapyridine and the like),immunosuppressive agent, steroidal drug (prednisolone,methylprednisolone, dexamethasone, hydrocortisone and the like) ornonsteroidal anti-inflammatory drug and the like. The immunosuppressiveagent is particularly preferably the one selected from azathioprine,cyclophosphamide, methotrexate, brequinar sodium, deoxyspergualin,mizoribine, 2-morpholinoethyl mycophenolate, cyclosporin, rapamycin,tacrolimus hydrate, leflunomide, OKT-3, anti TNF-α antibody, anti IL-6antibody and FTY720 (EP627406-B1). The nonsteroidal anti-inflammatorydrug is exemplified by aspirin, indomethacin, indomethacin farnesil,diclofenac sodium, alclofenac, amfenac sodium, ibuprofen, ketoprofen,loxoprofen sodium, naproxen, pranoprofen, zaltoprofen, mefenamic acid,flufenamic acid, tolufenamic acid, phenylbutazone, ketophenylbutazone,piroxicam, tenoxicam, ampiroxicam and the like.

As mentioned above, the compound of the present invention and apharmaceutically acceptable salt thereof have a novel action mechanism,which is different from that of existing antirheumatic drugs,immunosuppressive agents, steroidal drugs, nonsteroidalanti-inflammatory drugs and the like used for the treatment of variousautoimmune diseases. Thus, they are expected to show a synergisticaction when combined with the above-mentioned existing pharmaceuticalagents.

When the compound of the present invention or a pharmaceutically saltthereof is used as a pharmaceutical agent, the inventive compound isadmixed with a pharmaceutically acceptable carrier (e.g., excipient,binder, disintegrator, corrective, corrigent, emulsifier, diluent,solubilizer and the like) to give a pharmaceutical composition orpharmaceutical preparation, which is formulated into tablet, pill,capsule, granule, powder, syrup, emulsion, elixir, suspension, solution,injection, infusion, eye drop, eye ointment, suppository, ointment,lotion and the like and administered orally or parenterally.

A pharmaceutical composition can be formulated according to a typicalmethod. In the present specification, the “parenteral” includessubcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection, drip, instillation and the like. Apreparation for injection such as sterile aqueous suspension forinjection and oily suspension for injection can be prepared according tothe method known in this field using a suitable dispersing agent,moisturizing agent or suspending agent. The sterile preparation forinjection may be a sterile injectable solution or suspension in anontoxic, parenterally administrable diluent or solvent such as anaqueous solution and the like. Examples of usable vehicle and solventinclude water, Ringer solution, isotonic brine and the like. It is alsopossible to use sterile nonvolatile oil as a typical solvent orsuspending solvent. Any nonvolatile oil or fatty acid can be used forthis end, which may be natural, synthetic or semi-synthetic fatty oil orfatty acid, or natural, synthetic or semi-synthetic mono, di ortri-glycerides. When an injection is prepared, a suitable suspendingagent, nonionic surfactant, solubilizer and the like may be combined asnecessary. Suppositories for intrarectal administration can be producedby admixing a drug with a suitable nonirritative excipient, such ascocoa butter and polyethylene glycols, and the like that are solid atnormal temperature but become liquid at the temperature in the intestineand melt in rectum to release the drug. The solid dosage form for oraladministration includes the above-mentioned powder, granule, tablet,pill, capsule and the like. In such a dosage form, the active ingredientcompound can contain at least one additive such as sucrose, lactose,cellulose sugar, mannitol, maltitol, dextran, starches, agar, arginates,chitins, chitosans, pectines, tragacanth, gum arabic, gelatins,collagens, casein, albumin, synthetic or semi-synthetic polymers andglycerides. Such dosage product can generally contain other additivessuch as inert diluent, lubricants such as magnesium stearate,preservatives such as parabens, sorbins and the like, antioxidant suchas ascorbic acid, α-tocopherol, cysteine and the like, disintegrators,binders, thickeners, buffer agent, sweetener, flavors, perfumes and thelike. Tablets and pills may be further enteric-coated. A liquid agentfor oral administration may be those approved as medicines, such asemulsion, syrup, elixir, suspension, solution and the like, which maycontain an inert diluent generally used in this field, such as water andthe like. When preparing an eye drop, an aqueous liquid or aqueoussolution, particularly a sterile injectable aqueous solution is used.Such liquid for instillation may contain various additives asappropriate, such as buffer, isotonicity agent, solubilizer,preservative, thickener, chelating agent, pH adjusting agent, flavor andthe like. When an ointment is prepared, an oleaginous base, an emulsionbase, a water-soluble base, a suspension base and the like are used, anda dissolution/absorption accelerator can be also added as appropriate.When a lotion is prepared, the compound is dispersed in a liquid mediumor partially dissolved therein and admixed with emulsifier,dissolution/absorption accelerator, thickener and stabilizer asappropriate.

Moreover, by combining the compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt thereof with one or morepharmaceutical agents selected from an antirheumatic drug, animmunosuppressive agent, a steroidal drug and a nonsteroidalanti-inflammatory drug, a superior therapeutic effect can be expected.As used herein, by the “combination” is meant a combination compositionof the compound of the present invention or a pharmaceuticallyacceptable salt thereof, with one or more pharmaceutical agents selectedfrom an antirheumatic drug, an immunosuppressive agent, a steroidal drugand a nonsteroidal anti-inflammatory drug, and the use as an enhancer ofthe effect of one or more pharmaceutical agents selected from anantirheumatic drug, an immunosuppressive agent, a steroidal drug and anonsteroidal anti-inflammatory drug, which enhancer contains thecompound of the present invention or a pharmaceutically acceptable saltthereof. It also includes simultaneous or time interval use of two ormore active ingredient compounds upon mixing or without mixing, as wellas use upon combination and the combination. The medicine of the presentinvention characterized by the combination of the above-mentionedcompound of the formula (I) or a pharmaceutically acceptable saltthereof with one or more pharmaceutical agents selected from anantirheumatic drug, an immunosuppressive agent, a steroidal drug and anonsteroidal anti-inflammatory drug is free of any particular limitationas long as the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof is combined with one or morepharmaceutical agents selected from an antirheumatic drug, animmunosuppressive agent, a steroidal drug and a nonsteroidalanti-inflammatory drug. For example, (A) a compound of the formula (I)or a pharmaceutically acceptable salt thereof, and (B) one or morepharmaceutical agents selected from an antirheumatic drug, animmunosuppressive agent, a steroidal drug and a nonsteroidalanti-inflammatory drug may be set to give a preparation for generaladministration, or they may be admixed in advance to give a composition.The combination medicine of the present invention may be obtained by,for example, mixing a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutical agents selectedfrom an antirheumatic drug, an immunosuppressive agent, a steroidal drugand a nonsteroidal anti-inflammatory drug according to a knownproduction method for producing a pharmaceutical preparation, whileusing a pharmaceutically acceptable diluent, excipient and the like, togive a single preparation. Alternatively, they may be respectivelyprepared into a preparation using a pharmaceutically acceptable diluent,excipient and the like on demand, or into a combined preparation (set,kit, pack) containing respective agents prepared separately in onecontainer. For example, the combination medicine of the presentinvention may be (1) a combination preparation wherein a preparation,which may be independent or in combination, containing a compound of theformula (I) or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutical agents selected from an antirheumatic drug, animmunosuppressive agent, a steroidal drug and a nonsteroidalanti-inflammatory drug are packaged, or (2) a composition containing acompound of the formula (I) or a pharmaceutically acceptable saltthereof and one or more pharmaceutical agents selected from anantirheumatic drug, an immunosuppressive agent, a steroidal drug and anonsteroidal anti-inflammatory drug.

The administration route of the combination medicine of the presentinvention is the same as the administration route of the above-mentionedmedicine containing the compound of the present invention, which may bean oral administration or parenteral administration and determined inconsideration of concrete target disease site and the like. When thecompound of the present invention or a pharmaceutically acceptable saltthereof and one or more pharmaceutical agents selected from anantirheumatic drug, an immunosuppressive agent, a steroidal drug and anonsteroidal anti-inflammatory drug are prepared separately, these maybe administered separately, simultaneously or at time intervals to asingle subject via the same route or different routes. When thecombination medicine of the present invention is administered, thecompound of the present invention or a pharmaceutically acceptable saltthereof, and one or more pharmaceutical agents selected from anantirheumatic drug, an immunosuppressive agent, a steroidal drug and anonsteroidal anti-inflammatory drug are each prepared by theabove-mentioned conventional method and used for administration.

When the compound of the present invention or a pharmaceuticallyacceptable salt thereof is used as a medicine or a combination medicine,the dose is determined in consideration of the age, body weight, generalhealth condition, sex, diet, administration time, administration method,clearance rate, combination of drugs, level of disease for which thepatient is under treatment and other factors.

The compound of the present invention and pharmaceutically acceptablesalts thereof are low toxic and can be used safely. When the compound ora pharmaceutically acceptable salt thereof is used alone, the daily dosevaries depending on the conditions and body weight of patients, the kindof the compound, administration route and the like. In the case ofparenteral use, it is about 0.01–100 mg/person/day, preferably 0.01–500mg/person/day for subcutaneous injection, intravenous injection,intramuscular injection and intrarectal injection, and in case of oraluse, it is about 0.01–1000 mg/person/day, preferably 0.01–500mg/person/day.

When the compound of the present invention or a pharmaceuticallyacceptable salt thereof is used as a combination medicine, the dailydose varies depending on the condition and body weight of patients, thekind of the compound, administration route and the like. For example, itis administered parenterally in a dose of about 0.01–100 mg/person/day,preferably 0.01–10 mg/person/day, subcutaneously, intravenously,intramuscularly or intrarectally, or orally in a dose of about 0.01–1000mg/person/day, preferably 0.01–100 mg/person/day. When an antirheumaticdrug, an immunosuppressive agent, a steroidal drug or a nonsteroidalanti-inflammatory drug is used as a combination medicine, the daily dosevaries depending on the condition and body weight of patients, the kindof the compound, administration route and the like. For example, it isadministered parenterally in a dose of about 0.001–500 mg/person/day,preferably 0.001–50 mg/person/day, subcutaneously, intravenously,intramuscularly or intrarectally, or orally in a dose of about0.001–5000 mg/person/day, preferably 0.001–500 mg/person/day.

BEST MODE OF EMBODIMENT OF THE INVENTION

The present invention is explained in more detail in the following byway of Starting Material Synthesis Examples, Examples, FormulationExample and Experimental Examples that do not limit the presentinvention in any way. In the Examples, Me means methyl, Et means ethyl,iPr means isopropyl, tBu means tert-butyl, TBDMS meanstert-butyldimethylsilyl and DMF means dimethylformamide.

Starting Material Synthesis Example 11-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid

4-Fluorophenylhydrazine (15.5 g) and ethyl 2-ethoxymethyleneacetoacetate(22.9 g) synthesized according to the method described in J. Chem. Soc.Perkin trans. I, p. 1875, 1988 were stirred in ethanol (200 ml) at arefluxing temperature for 2 h. After the evaporation of the solvent, theresidue was recrystallized from a mixed solvent of ethylacetate-n-hexane to give ethyl1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (17.7 g), meltingpoint: 48–49° C.

Then, ethyl 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (17.7 g)and sodium hydroxide (3.5 g) were added to a mixed solvent of ethanol(80 ml)-water (80 ml), and the mixture was stirred at a refluxingtemperature for 2 h. After the reaction, ethanol was evaporated anddilute hydrochloric acid was added. The mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was evaporated. The residue was recrystallized fromethyl acetate to give the title compound (12.3 g), melting point:165–166° C.

Starting Material Synthesis Example 21-Phenyl-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that phenylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:118° C.

Starting Material Synthesis Example 31-(4-Methylphenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 4-methylphenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 203° C.

Starting Material Synthesis Example 41-(2,4-Difluorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 2,4-difluorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 183–184° C.

Starting Material Synthesis Example 51-(2-Chloro-5-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that2-chloro-5-trifluoromethylphenylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:124–125° C.

Starting Material Synthesis Example 61-(4-Methoxyphenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 4-methoxyphenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 213–214° C.

Starting Material Synthesis Example 71-(3-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 3-trifluoromethylphenylhydrazine wasused instead of 4-fluorophenylhydrazine, the title compound wasobtained, melting point: 153–154° C.

Starting Material Synthesis Example 81-(4-Chlorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 4-chlorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 199–200° C.

Starting Material Synthesis Example 9 1,5-Dimethylpyrazole-4-carboxylicacid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that methylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:230° C. (decomposition).

Starting Material Synthesis Example 10 5-Methylpyrazole-4-carboxylicacid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that hydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:223° C.

Starting Material Synthesis Example 111-Cyclohexyl-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that cyclohexylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:153–154° C.

Starting Material Synthesis Example 121-tert-Butyl-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that tert-butylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:213–214° C.

Starting Material Synthesis Example 131-(2-Hydroxyethyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 2-hydroxyethylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 203° C.

Starting Material Synthesis Example 141-(2,2,2-Trifluoroethyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that (2,2,2-trifluoroethyl)hydrazine wasused instead of 4-fluorophenylhydrazine, the title compound wasobtained, melting point: 188–190° C.

Starting Material Synthesis Example 151-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1) Ethyl5-amino-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate

4-Fluorophenylhydrazine (25 g) and ethyl2-cyano-3-ethoxy-3-methylacrylate (32 g) were stirred in ethanol (130ml) at a refluxing temperature for 3 h. The solvent was evaporated anddiisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from a mixed solvent of ethylacetate-n-hexane to give the title compound (10.7 g), melting point:129–131° C.

(2) Ethyl 1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate

To a tetrahydrofuran solution (50 ml) containing ethyl5-amino]1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate (10.5 g) wasadded isoamyl nitrite (14 g) and the mixture was stirred at a refluxingtemperature for 2 h. The mixture was treated with aqueous potassiumcarbonate solution and extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. n-Hexane was added to the obtainedresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-n-hexane to give the title compound(7.8 g), melting point: 103–104° C.

(3) 1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid

To a mixed solvent of ethanol (40 ml) and water (40 ml) were added ethyl1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate (8.5 g) and sodiumhydroxide (1.66 g), and the mixture was stirred at a refluxingtemperature for 2 h. After the reaction, ethanol was evaporated and tothe residue was added dilute hydrochloric acid. The obtained solid wasrecrystallized from aqueous methanol solution to give the titlecompound, melting point: 194–195° C.

Starting Material Synthesis Example 161-Phenyl-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that phenylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:194–195° C.

Starting Material Synthesis Example 171-(2,4-Difluorophenyl)-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that 2,4-difluorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 245–247° C.

Starting Material Synthesis Example 181-(4-Methoxyphenyl)-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that 4-methoxyphenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 176–178° C.

Starting Material Synthesis Example 191-(2-Chloro-5-trifluoromethylphenyl)-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that2-chloro-5-trifluoromethylphenylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:206–208° C.

Starting Material Synthesis Example 201-(3-Trifluoromethylphenyl)-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that 3-trifluoromethylphenylhydrazine wasused instead of 4-fluorophenylhydrazine, the title compound wasobtained, melting point: 166–168° C.

Starting Material Synthesis Example 21 1,3-Dimethylpyrazole-4-carboxylicacid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that methylhydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:191–192° C.

Starting Material Synthesis Example 221-(4-Fluorophenyl)pyrazole-4-carboxylic acid (1) Ethyl5-amino-1-(4-fluorophenyl) pyrazole-4-carboxylate

4-Fluorophenylhydrazine (20 g) and ethyl 2-cyano-3-ethoxyacrylate (26.7g) were added to ethanol (200 ml), and the mixture was stirred at arefluxing temperature for 1 h. After cooling, the precipitated crystalswere recrystallized from aqueous ethanol solution to give the titlecompound (38.9 g), melting point: 154–155° C.

(2) Ethyl 1-(4-fluorophenyl)pyrazole-4-carboxylate

Ethyl 5-amino-1-(4-fluorophenyl)pyrazole-4-carboxylate (15 g) wasdissolved in tetrahydrofuran (150 ml) and isoamyl nitrite (21.2 g) wasadded. The mixture was stirred at a refluxing temperature for 2 h. Aftercooling, the precipitated crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (10.6 g).

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.37(3H, dd, J=6.6, 7.3 Hz), 4.33(2H, dd,J=6.6, 7.3 Hz),7.14–7.19(2H, m), 7.63–7.70(2H, m), 8.01(1H, s), 8.34(1H,

(3) 1-(4-Fluorophenyl)pyrazole-4-carboxylic acid

Ethyl 1-(4-fluorophenyl)pyrazole-4-carboxylate (10.6 g) was dissolved ina mixed solvent of ethanol (80 ml) and water (80 ml), and sodiumhydroxide (2.2 g) was added. The mixture was stirred at a refluxingtemperature for 30 min. After evaporation of ethanol, dilutehydrochloric acid was added to the residue. The obtained solid wasrecrystallized from aqueous methanol solution to give the title compound(8.9 g), melting point: 244–247° C.

Starting Material Synthesis Example 231-(2,2,2-Trifluoroethyl)pyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 22, except that 2,2,2-trifluoroethylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 160–162° C.

Starting Material Synthesis Example 24 Pyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 22, except that hydrazine was used instead of4-fluorophenylhydrazine, the title compound was obtained, melting point:227–228° C.

Starting Material Synthesis Example 255-Chloro-1-(4-fluorophenyl)pyrazole-4-carboxylic acid

Ethyl 5-amino-1-(4-fluorophenyl)pyrazole-4-carboxylate (5.4 g) wasdissolved in 12N hydrochloric acid, and aqueous solution (10 ml)containing sodium nitrite (4.5 g) was added dropwise thereto underice-cooling, which was followed by stirring for 2 h. An aqueous solution(10 ml) containing copper(I) chloride (10.7 g) was added and the mixturewas stirred for 30 min. The mixture was warmed to room temperature andstirred further for 2 h. Solid was filtered off with Celite and ethylacetate was added to the filtrate to separate the organic layer. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the obtained residue to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-n-hexane to give ethyl5-chloro-1-(4-fluorophenyl)pyrazole-4-carboxylate (3.5 g), meltingpoint: 70–72° C.

Ethyl 5-chloro-1-(4-fluorophenyl) pyrazole-4-carboxylate (3.5 g) wasdissolved in a mixed solvent of ethanol (30 ml) and water (30 ml).Sodium hydroxide (0.62 g) was added and the mixture was stirred at arefluxing temperature for 30 min. Ethanol was evaporated and dilutehydrochloric acid was added. The obtained solid was recrystallized froman aqueous methanol solution to give the title compound (2.9 g), meltingpoint: 230–231° C.

Starting Material Synthesis Example 26 Ethyl1-(4-fluorophenyl)-5-hydroxypyrazole-4-carboxylate

To ethanol (30 ml) were added 4-fluorophenylhydrazine (7.75 g) and ethylethoxymethylenemalonate (2.5 g), and the mixture was refluxed for 3 h.The solvent was evaporated under reduced pressure and diisopropyl etherwas added to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-diisopropyl etherto give the title compound (2.5 g), melting point: 127–128° C.

Starting Material Synthesis Example 271-(4-Fluorophenyl)-3,5-dimethylpyrazole-4-carboxylic acid

4-Fluorophenylhydrazine (7.75 g) and ethyl diacetoacetate (10.6 g) wereadded to ethanol (30 ml) and the mixture was refluxed for 3 h. Thesolvent was evaporated under reduced pressure and diisopropyl ether wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-diisopropyl etherto give ethyl 1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylate(15.5 g), melting point: 59–60° C.

Then, ethyl 1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylate (15.5g) was dissolved in a mixed solvent of ethanol (30 ml) and water (30ml). Sodium hydroxide (2.75 g) was added and the mixture was stirred ata refluxing temperature for 30 min. After evaporation of ethanol, dilutehydrochloric acid was added to the residue. The obtained solid wasrecrystallized from aqueous methanol solution to give the title compound(11.5 g), melting point: 219–220° C.

Starting Material Synthesis Example 28 Ethyl1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate and ethyl1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate

To ethanol (30 ml) were added 4-fluorophenylhydrazine (5 g) and ethyl2,4-dioxovalerate (10.6 g) and the mixture was refluxed for 3 h. Thesolvent was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (mobile phase:chloroform) to give ethyl1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate (2 g) and ethyl1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate (3 g).

Ethyl 1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate:

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.37(3H,t, J=7.3 Hz), 2.34(3H, s),4.22(2H, q, J=7.3 Hz), 6.80(1H, s), 7.08–7.14(2H, m), 7.35–7.40(2H, m)

Ethyl 1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate:

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.39(3H, dd, J=6.6, 7.3 Hz), 2.30(3H, s),4.41(2H, dd, J=6.6, 7.3 Hz), 6.73(1H, s), 7.13–7.19(2H, m),7.41–7.46(2H, m)

Starting Material Synthesis Example 291-(4-Fluorophenyl)-3-methylpyrazole-5-carboxylic acid

Ethyl 1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate (2 g) wasdissolved in a mixed solvent of ethanol (10 ml) and water (10 ml) andsodium hydroxide (0.4 g) was added. The mixture was stirred at arefluxing temperature for 30 min. Ethanol was evaporated and to theresidue was added dilute hydrochloric acid. The obtained solid wasrecrystallized from aqueous methanol solution to give the title compound(1.4 g), melting point: 188° C.

Starting Material Synthesis Example 301-(4-Fluorophenyl)-5-methylpyrazole-3-carboxylic acid

Ethyl 1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate (3 g) wasdissolved in a mixed solvent of ethanol (15 ml) and water (15 ml) andsodium hydroxide (0.6 g) was added. The mixture was stirred at arefluxing temperature for 30 min. Ethanol was evaporated and to theresidue was added dilute hydrochloric acid. The obtained solid wasrecrystallized from aqueous methanol solution to give the title compound(2.1 g), melting point: 177° C.

Starting Material Synthesis Example 31 Methyl1-methyl-3-phenylpyrazole-5-carboxylate and methyl1-methyl-5-phenylpyrazole-3-carboxylate

Methyl 4-phenyl-2,4-dioxobutanoate (10 g) obtained by acetophenone anddimethyl oxalate as starting materials and methylhydrazine were reactedin ethanol (60 ml) at a refluxing temperature for 1 h. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography (mobile phase:dichloromethane) togive methyl 1-methyl-3-phenylpyrazole-5-carboxylate (3.0 g) and methyl1-methyl-5-phenylpyrazole-3-carboxylate (3.6 g).

Methyl 1-methyl-3-phenylpyrazole-5-carboxylate:

melting point: 54–56° C.

Methyl 1-methyl-5-phenylpyrazole-3-carboxylate:

¹H-NMR(270 MHz, CDCl₃) δ(ppm):3.93(3H, s), 3.94(3H, s), 6.84(1H, s),7.33–7.48(5H, m)

Starting Material Synthesis Example 321-Methyl-3-phenylpyrazole-5-carboxylic acid

Methyl 1-methyl-3-phenylpyrazole-5-carboxylate (3 g) was dissolved in amixed solvent of ethanol (20 ml) and water (20 ml) and sodium hydroxide(0.7 g) was added. The mixture was stirred at a refluxing temperaturefor 30 min. Ethanol was evaporated and to the residue was added dilutehydrochloric acid. The obtained solid was recrystallized from aqueousmethanol solution to give the title compound (0.8 g), melting point:189° C.

Starting Material Compound 33 1-Methyl-5-phenylpyrazole-3-carboxylicacid

Methyl 1-methyl-5-phenylpyrazole-3-carboxylate (3.6 g) was dissolved ina mixed solvent of ethanol (20 ml) and water (20 ml) and sodiumhydroxide (0.8 g) was added. The mixture was stirred at a refluxingtemperature for 30 min. Ethanol was evaporated and to the residue wasadded dilute hydrochloric acid. The obtained solid was recrystallizedfrom aqueous methanol solution to give the title compound (2.2 g),melting point: 149–150° C.

Starting Material Synthesis Example 341-(4-Fluorophenyl)pyrrole-2-carboxylic acid and1-(4-fluorophenyl)pyrrole-3-carboxylic acid

(1) 4-Fluoroaniline (100 g) and 2,5-dimethoxytetrahydrofuran (124.9 g)were added to acetic acid (500 ml) and the mixture was stirred at arefluxing temperature for 1 h. After cooling to room temperature, thereaction mixture was added to water (2.5 Liters) and the mixture wasstirred further for 30 min. The precipitated crystals wererecrystallized from a mixed solvent of methanol-acetone (ratio=2:1) togive 1-(4-fluorophenyl)pyrrole (156 g), melting point: 57–58° C.

(2) Phosphorus oxychloride (96.5 g) was added dropwise under ice-coolingto dimethylformamide (600 ml) containing 1-(4-fluorophenyl)pyrrole (101g) over 1 h, and the mixture was stirred for 2 h and at room temperaturefor one day. The reaction mixture was added to 3 Liters of aqueoussolution containing potassium carbonate (130 g) and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof toluene-diisopropyl ether (ratio=1:10) to give1-(4-fluorophenyl)-2-formylpyrrole (43 g), melting point: 82–83° C.

(3) Potassium permanganate (30.1 g) and sodium hydroxide (15.3 g) wereadded to a solution of dimethylformamide (380 ml) and pyridine (300 ml),and 1-(4-fluorophenyl)-2-formylpyrrole (30 g) was further added theretounder ice-cooling with stirring. The mixture was warmed to roomtemperature and stirred further for 3 h. The reaction mixture wasfiltrated and the filtrate was neutralized with hydrochloric acid. Theprecipitated crystals were recrystallized from hydrous ethanol to give1-(4-fluorophenyl)pyrrole-2-carboxylic acid (20 g), melting point195–196° C.

(4) Trifluoromethanesulfonic acid (127 ml) was added dropwise to adichloroethane solution (680 ml) containing1-(4-fluorophenyl)-2-formylpyrrole (68 g) at room temperature, and themixture was stirred at a refluxing temperature for 5 h. After cooling toroom temperature, the reaction mixture was poured into aqueous potassiumcarbonate solution and extracted with chloroform. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. Theobtained residue was purified by column chromatography (mobilephase:methylene chloride) to give 1-(4-fluorophenyl)-3-formylpyrrole (13g).

(5) Potassium permanganate (13 g) and sodium hydroxide (6.6 g) wereadded to a solution of dimethylformamide (150 ml) and pyridine (130 ml),and 1-(4-fluorophenyl)-3-formylpyrrole (30 g) was added thereto underice-cooling with stirring. The mixture was warmed to room temperatureand stirred further for 3 h. The reaction mixture was filtrated and thefiltrate was neutralized with hydrochloric acid. The precipitatedcrystals were recrystallized from hydrous ethanol to give1-(4-fluorophenyl)pyrrole-3-carboxylic acid (9.2 g), melting point204–205° C.

Starting Material Synthesis Example 35 2-Chloro-5-nitrobenzonitrile

2-Chloro-5-nitrobenzoic acid (500 g) was added to a mixed solvent ofdimethylformamide (500 ml) and toluene (1.5 Liters). Thionyl chloride(217 ml) was added thereto at room temperature with stirring and themixture was stirred at a refluxing temperature for 3 h. The reactionmixture was then ice-cooled and added dropwise to 28% aqueous amonia(750 ml). The mixture was stirred further for 1 h. The precipitatedcrystals were collected by filtration, and the crystals wererecrystallized from hydrous ethanol to give 2-chloro-5-nitrobenzamide(346 g), melting point: 177–179° C.

Further, 2-chloro-5-nitrobenzamide (100 g) was added todimethylformamide (240 ml) and pyridine (100 ml). To the mixture wasdropwise added benzenesulfonyl chloride at room temperature withstirring, and the mixture was stirred at 145° C. for 3 h. The reactionmixture was ice-cooled, and water (240 ml) was added thereto. Theprecipitated crystals were recrystallized from hydrous ethanol to give2-chloro-5-nitrobenzonitrile (81.3 g), melting point: 108–110° C.

Starting Material Synthesis Example 365-Amino-2-neopentyloxybenzonitrile

To dimethylformamide solution (364 ml) containing2-chloro-5-nitrobenzonitrile (91 g) and neopentyl alcohol (52 g) wasadded sodium hydride (60% content, 27.8 g) under ice-cooling and themixture was stirred for 1 h. The reaction mixture was poured into waterand extracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. Diisopropyl ether wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-n-hexane to give5-nitro-2-neopentyloxybenzonitrile (105 g), melting point: 90–91° C.

Subsequently, Ammonium chloride (10 g) and iron powder (75 g) were addedto a mixed solvent of water (286 ml) and ethanol (753 ml), and themixture was heated to 65° C. Then, 5-nitro-2-neopentyloxybenzonitrile(80.5 g) was added in parts over 20 min and the mixture was stirred at arefluxing temperature for 30 min. After ice-cooling, the reactionmixture was filtrated and the solvent was evaporated under reducedpressure. To the residue was added aqueous sodium hydroxide solution andthe mixture was extracted with toluene. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate, afterwhich the solvent was evaporated under reduced pressure. Diisopropylether was added to the residue to allow crystallization. The crystalswere recrystallized from a mixed solvent of ethyl acetate-n-hexane togive the title compound (70 g), melting point: 55–56° C.

Starting Material Synthesis Example 37 3-Bromo-4-neopentyloxyaniline

To dimethylformamide solution (78 ml) containing 4-chloronitrobenzene(15.7 g) and neopentyl alcohol (10.6 g) was added by portions sodiumhydride (60% content, 4.8 g) under ice-cooling. The mixture was stirredunder ice-cooling for 1 h. The mixture was warmed to room temperatureand stirred further for 1 h. The reaction mixture was poured into waterand extracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. The obtained oilysubstance was distilled under reduced pressure to give4-neopentyloxynitrobenzene (69 g), boiling point: 120–125° C./0.1 mmHg.

Subsequently, a catalytic amount of potassium iodide was added to4-neopentyloxynitrobenzene (69 g), and bromine (66 g) was added dropwiseat 60° C. The mixture was stirred for 5 h. The reaction mixture waspoured into water and extracted with toluene. The organic layer waswashed with aqueous sodium sulfite solution, dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was recrystallized from n-hexane to give3-bromo-4-neopentyloxynitrobenzene (80 g), melting point: 86–88° C.

Furthermore, ammonium chloride (10 g) and iron powder (75 g) were addedto a mixed solvent of water (286 ml) and ethanol (753 ml), and themixture was heated to 65° C. 3-Bromo-4-neopentyloxynitrobenzene (80 g)was added in parts over 20 min and the mixture was stirred at arefluxing temperature for 30 min. The reaction mixture was ice-cooledand filtrated. The solvent was evaporated under reduced pressure. To theresidue was added sodium hydroxide and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (70 g),melting point: 45° C.

Starting Material Synthesis Example 38 EthylN-(3-cyano-4-neopentyloxyphenyl)glycine

To a tetrahydrofuran solution (90 ml) containing5-amino-2-neopentyloxybenzonitrile (30 g) and triethylamine (17.7 g) wasadded tert-butoxycarboxylic anhydride (35.2 g) under ice-cooling. Themixture was warmed to room temperature and stirred further for 4 h. Thereaction mixture was poured into aqueous potassium carbonate solutionand extracted with chloroform. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, after which thesolvent was evaporated under reduced pressure. n-Hexane was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-n-hexane to giveN-(3-cyano-4-neopentyloxyphenyl)-tert-butoxycarboxamide (24.5 g),melting point: 169–170° C.

To dimethylformamide solution (240 ml) containingN-(3-cyano-4-neopentyloxyphenyl)-tert-butoxycarboxamide (24.5 g) wasadded sodium hydride (60% content, 1.15 g) under ice-cooling and themixture was stirred for 30 min. The mixture was warmed to roomtemperature and stirred further for 1 h. The reaction mixture wasice-cooled and ethyl bromoacetate (24.5 g) was added, which was followedby stirring for 1 h. The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with 0.1Nhydrochloric acid and saturated brine, and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase: chloroform) to give ethylN-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)glycine (36.5 g)as an oily substance. The obtained ethylN-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)glycine (8.2 g)was added to trifluoroacetic acid (24 ml) at room temperature and themixture was stirred for 1 h. The reaction mixture was poured into anaqueous potassium carbonate solution and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, after which the solvent was evaporated. Theresidue was purified by silica gel column chromatography (mobile phase:chloroform) to give the title compound (5.9 g), melting point: 78° C.

Starting Material Synthesis Example 39 Ethyl4-(3-cyano-4-neopentyloxyphenyl)aminobutyrate

To dimethylformamide solution (50 ml) containingN-(3-cyano-4-neopentyloxyphenyl)-tert-butoxycarboxamide (5 g) was addedsodium hydride (60% content, 0.79 g), and the mixture was stirred for 30min under ice-cooling. The mixture was warmed to room temperature andstirred further for 1 h. The reaction mixture was ice-cooled and ethylbromobutyrate (4.17 g) was added. The mixture was stirred for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with 0.1N hydrochloric acid and saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (mobile phase: chloroform) to giveethyl 4-[N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)]butyrate(7.2 g) as an oily substance. The obtained ethyl4-[N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)]butyrate (7.2g) was added to trifluoroacetic acid (24 ml) at room temperature and themixture was stirred for 1 h. The reaction mixture was poured intoaqueous potassium carbonate solution and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, after which the solvent was evaporated. Theresidue was purified by silica gel column chromatography (mobile phase:chloroform) to give the title compound (5.7 g), melting point: 88° C.

Starting Material Synthesis Example 40 5-Amino-2-piperidinobenzonitrile

2-Chloro-5-nitrobenzonitrile (20 g) and piperidine (9.34 g) were addedto ethanol (100 ml) and the mixture was stirred at a refluxingtemperature for 1 h. The solvent was evaporated under reduced pressureand diisopropyl ether was added to the residue to allow crystallization.The crystals were recrystallized from hydrous ethanol to give5-nitro-2-piperidinobenzonitrile (17 g), melting point 75° C.

Ammonium chloride (1.6 g) and iron powder (8.4 g) were added to a mixedsolvent of water (40 ml) and ethanol (120 ml), and the mixture washeated to 65° C. Then, 5-nitro-2-piperidinobenzonitrile (10 g) was addedin parts over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution, and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (8.3 g), melting point: 148–149° C.

Starting Material Synthesis Example 415-Amino-2-(4-hydroxypiperidin-1-yl)benzonitrile

2-chloro-5-nitrobenzonitrile (36 g) and 4-hydroxypiperidine (50 g) wereadded to ethanol (300 ml), and the mixture was stirred at a refluxingtemperature for 1 h. The solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous ethanol to give5-nitro-2-(4-hydroxypiperidin-1-yl)benzonitrile (37.4 g), melting point:114–115° C.

Ammonium chloride (1.2 g) and iron powder (6.3 g) were added to a mixedsolvent of water (16 ml) and ethanol (48 ml), and the mixture was heatedto 65° C. Then, 5-nitro-2-(4-hydroxypiperidino)benzonitrile (10 g) wasadded in parts over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (4.5 g), melting point: 144–145° C.

Starting Material Synthesis Example 425-Amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile

2-Chloro-5-nitrobenzonitrile (15 g) and piperazinoethanol (16 g) wereadded to ethanol (100 ml) and the mixture was stirred at a refluxingtemperature for 1 h. The solvent was evaporated under reduced pressure.To the residue was added aqueous sodium hydroxide solution and themixture was extracted with chloroform. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, after which thesolvent was evaporated under reduced pressure. To the residuediisopropyl ether was added to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give5-nitro-2-(2-hydroxyethylpiperazin-1-yl)benzonitrile (18.7 g), meltingpoint 100–102° C.

Ammonium chloride (1.5 g) and iron powder (13.8 g) were added to a mixedsolvent of water (51 ml) and ethanol (170 ml), and the mixture washeated to 65° C. Then,5-nitro-2-(2-hydroxyethylpiperazin-1-yl)benzonitrile (17 g) was added inparts over 20 min and the mixture was stirred at a refluxing temperaturefor 30 min. The reaction mixture was ice-cooled and filtrated. Thesolvent was evaporated under reduced pressure. To the residue was addedaqueous sodium hydroxide solution and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (13 g),melting point: 137–138° C.

Starting Material Synthesis Example 43 5-Amino-2-morpholinobenzonitrile

2-Chloro-5-nitrobenzonitrile (16.7 g) and morpholine (16 g) were addedto ethanol (300 ml) and the mixture was stirred at a refluxingtemperature for 1 h. The solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous ethanol to give5-nitro-2-morpholinobenzonitrile (19.7 g), melting point: 138–140° C.

Ammonium chloride (2 g) and iron powder (18.9 g) were added to a mixedsolvent of water (65 ml) and ethanol (197 ml), and the mixture washeated to 65° C. Then, 5-nitro-2-morpholinobenzonitrile (19.7 g) wasadded in parts over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (12.9 g), melting point: 147–148° C.

Starting Material Synthesis Example 445-Amino-2-diethylaminobenzonitrile

2-Chloro-5-nitrobenzonitrile (15 g) and diethylamine (15 g) were addedto ethanol (100 ml) and the mixture was stirred at a refluxingtemperature for 1 h. The solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous ethanol to give5-nitro-2-diethylaminobenzonitrile (15.6 g), melting point: 98° C.

Ammonium chloride (1.5 g) and iron powder (15.9 g) were added to a mixedsolvent of water (50 ml) and ethanol (150 ml), and the mixture washeated to 65° C. Then, 5-nitro-2-diethylaminobenzonitrile (15.6 g) wasadded in parts over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (12.1 g), melting point: 63–66° C.

Starting Material Synthesis Example 455-Amino-2-(4-methylpiperazin-1-yl)benzonitrile

2-Chloro-5-nitrobenzonitrile (15 g) and methylpiperazine (9.8 g) wereadded to ethanol (100 ml) and the mixture was stirred at a refluxingtemperature for 1 h. The solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous ethanol to give5-nitro-2-diethylaminobenzonitrile (12.7 g), melting point: 83–85° C.

Ammonium chloride (1.3 g) and iron powder (11.6 g) were added to a mixedsolvent of water (43 ml) and ethanol (130 ml), and the mixture washeated to 65° C. Then, 5-nitro-2-diethylaminobenzonitrile (12.7 g) wasadded in parts over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (8.1 g), melting point: 45–46° C.

Starting Material Synthesis Example 46 Ethyl1-(4-amino-2-cyanophenyl)piperidin-4-ylcarboxylate

2-Chloro-5-nitrobenzonitrile (10 g), ethyl isonipecotate (60 g) andsilver nitrate (11.1 g) were stirred at 120° C. for 3 h. The reactionmixture was cooled to room temperature and the solid was filtered off.To the filtrate was added dilute hydrochloric acid and the mixture wasextracted with ethyl acetate. The organic layer was washed with dilutehydrochloric acid and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous diisopropyl ether to giveethyl 1-(4-nitro-2-cyanophenyl)piperidin-4-ylcarboxylate (17.1 g).

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.28(3H, dd, J=6.6, 7.3 Hz), 1.94–2.15(4H,m), 2.55–2.62(1H, m), 3.21(2H, ddd, J=2.6, 4.3, 10.6 Hz), 3.88(2H, ddd,J=2.6, 4.3, 10.6 Hz), 4.15(2H, dd, J=6.6, 7.3 Hz), 6.98(1H, d, J=10.2Hz), 8.25(1H, dd, J=2.6, 10.2 Hz), 8.41(1H, d, J=2.6 Hz)

Ammonium chloride (2.1 g) and iron powder (11.1 g) were added to a mixedsolvent of water (110 ml) and ethanol (30 ml), and the mixture washeated to 65° C. Then, ethyl1-(4-nitro-2-cyanophenyl)piperidin-4-ylcarboxylate (17.1 g) was added inparts over 20 min and the mixture was stirred at a refluxing temperaturefor 30 min. The reaction mixture was ice-cooled and filtrated. Thesolvent was evaporated under reduced pressure. To the residue was addedaqueous sodium hydroxide solution, and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (12 g),melting point: 98° C.

Starting Material Synthesis Example 475-Amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzonitrile

2-Chloro-5-nitrobenzonitrile (31.4 g) and piperazine (44.5 g) were addedto acetonitrile (250 ml), and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was added to water andextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. The residue was recrystallizedfrom diisopropyl ether to give 5-nitro-2-piperazinebenzonitrile (48.8g). tert-Butoxycarboxylic anhydride (91.5 g) was added under ice-coolingto tetrahydrofuran (150 ml) containing 5-nitro-2-piperazinebenzonitrile(48.8 g) and triethylamine (25 g). The mixture was stirred for 30 minand at room temperature for 1 h. The precipitated crystals werecollected by filtration to give5-nitro-2-(4-tert-butoxycarbonylpiperazin-1-yl)benzonitrile (62.1 g),melting point:141–142° C.

Ammonium chloride (7.0 g) and iron powder (36.6 g) were added to a mixedsolvent of water (180 ml) and ethanol (540 ml), and the mixture washeated to 65° C. Then,5-nitro-2-(4-tert-butoxycarbonylpiperazin-1-yl)benzonitrile (62.1 g) wasadded in parts over 40 min and the mixture was stirred at a refluxingtemperature for 1 h. The reaction mixture was ice-cooled and filtrated.The solvent was evaporated under reduced pressure. To the residue wasadded aqueous sodium hydroxide solution, and the mixture was extractedwith toluene. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate, after which the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-n-hexane to give the title compound(50.7 g), melting point: 145° C.

Starting Material Synthesis Example 485-Amino-2-[4-(tertbutoxycarbonyl)homopiperazin-1-yl]benzonitrile

2-Chloro-5-nitrobenzonitrile (30.3 g) and homopiperazine (50 g) wereadded to acetonitrile (250 ml) and the mixture was stirred underice-cooling for 1 h. The reaction mixture was added to water andextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. The residue was recrystallizedfrom diisopropyl ether to give 5-nitro-2-homopiperazinebenzonitrile(32.4 g), melting point: 101° C.

tert-Butoxycarboxylic anhydride (70 g) was added under ice-cooling totetrahydrofuran (150 ml) containing 5-nitro-2-homopiperazinebenzonitrile(32.4 g) and triethylamine (21 g). The mixture was stirred for 30 minand at room temperature for 1 h. The precipitated crystals werecollected by filtration to give5-nitro-2-(4-tert-butoxycarbonylhomopiperazin-1-yl)benzonitrile (56 g),melting point: 98° C.

Ammonium chloride (5.9 g) and iron powder (32 g) were added to a mixedsolvent of water (160 ml) and ethanol (470 ml), and the mixture washeated to 65° C. Then,5-nitro-2-(4-tert-butoxycarbonylhomopiperazin-1-yl)benzonitrile (56 g)was added in parts over 30 min and the mixture was stirred at arefluxing temperature for 1 h. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (32 g), melting point: 38° C.

Starting Material Synthesis Example 49:Ethylcis-4-(4-amino-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate

2-Chloro-5-nitrobenzonitrile (13.3 g) and cis-2,6-dimethylpiperazine (25g) were added to acetonitrile (25 ml) and the mixture was stirred atroom temperature for 1 h. The reaction mixture was added to water andextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was recrystallized fromdiisopropyl ether to givecis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), meltingpoint: 109–110° C.

Then, cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g),potassium carbonate (4.9 g) and ethyl bromoacetate (6 g) were added todimethylformamide (35 ml), and the mixture was stirred at 60° C. for 1h. The reaction mixture was added to water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (mobile phase: chloroform) to give ethylcis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g)as an oily substance.

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.17(3H, s), 1.19(3H, s), 1.27(3H, t,J=7.3 Hz), 2.88(1H, d, J=3.3 Hz) 2.96(1H, d, J=3.3 Hz), 3.23(2H, ddd,J=2.6, 3.3, 4.0 Hz), 3.61(2H, s), 3.83(2H, dd, J=2.6, 4.0 Hz), 4.17(2H,q, J=7.3 Hz), 6.95 (1H, d, J=9.2 Hz), 8.21(1H, dd, J=2.5, 9.2 Hz),8.39(1H, d, J=2.5 Hz)

Ammonium chloride (1.2 g) and iron powder (6.1 g) were added to a mixedsolvent of water (90 ml) and ethanol (270 ml), and the mixture washeated to 65° C. Then, ethanol solution (20 ml) containing ethylcis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g)was dropwise added in parts over 20 min and the mixture was stirred at arefluxing temperature for 1 h. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. n-Hexane was added to the residueto allow crystallization. The crystals were recrystallized from a mixedsolvent of diisopropyl ether-n-hexane to give the title compound (9.5g), melting point: 45° C.

Starting Material Synthesis Example 50 5-Amino-2-isobutoxybenzonitrile

4-Nitrophenol (177 g), potassium carbonate (177 g) and isobutyl bromide(190 g) were added to dimethylformamide (500 ml) and the mixture wasstirred at 90° C. for 4 h. The reaction mixture was poured into water,and extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. The obtained oilysubstance was distilled under reduced pressure to give4-isobutoxynitrobenzene (203 g), boiling point: 125° C./0.15 mmHg

Subsequently, a catalytic amount of potassium iodide was added to4-isobutoxynitrobenzene (203 g) and the mixture was heated to 60° C.Bromine (183 g) was added dropwise over 3 h. The mixture was stirredfurther for 1 h. The reaction mixture was poured into water andextracted with toluene. The organic layer was washed with aqueous sodiumsulfite solution and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. The obtained oilysubstance was distilled under reduced pressure to give2-isobutoxy-5-nitrobromobenzene (248 g), boiling point: 135–140° C./0.25mmHg.

2-Isobutoxy-5-nitrobromobenzene (193 g) and copper cyanide (72 g) werereacted in dimethylformamide (419 ml) at 140° C. for 4 h. The reactionmixture was cooled to room temperature and the solid was filtered off.To the filtrate was added water, and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. The residue was recrystallized from diisopropylether to give 2-isobutyl-5-nitrobenzonitrile (20 g), melting point: 73°C.

Ammonium chloride (5.6 g) and iron powder (21 g) were added to a mixedsolvent of water (80 ml) and ethanol (240 ml), and the mixture washeated to 65° C. Then, 2-isobutyl-5-nitrobenzonitrile (20 g) was addedin parts over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (17 g), melting point: 88–93° C.

Starting Material Synthesis Example 51 5-Amino-2-isobutylbenzonitrile

4′-isobutylacetophenone (215 g) was added to 49% sulfuric acid (1 Liter)was and potassium bromate (268 g) was added under ice-cooling over 1.5h. The mixture was warmed to room temperature and stirred further for 1h, which was followed by extraction with toluene. The organic layer waswashed with water and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. The remainingoily substance was distilled under highly reduced pressure to give3′-bromo-4′-isobutylacetophenone (182 g), boiling point: 130–140°C./0.15 mmHg

3′-Bromo-4′-isobutylacetophenone (182 g) and copper cyanide (95.7 g)were stirred in dimethylformamide (520 ml) at 140° C. for 7 h. Thereaction mixture was cooled to room temperature and the solid wasfiltered off. To the filtrate was added water and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. The residue wasrecrystallized from n-hexane to give 3′-cyano-4′-isobutylacetophenone(70 g), melting point: 71–72° C.

Subsequently, 10% aqueous sodium hypochlorite solution (370 ml)containing sodium hydroxide (8 g) and methanol (5 ml) was heated to 60°C. 3′-Cyano-4′-isobutylacetophenone (20 g) was added thereto by portionsand the mixture was stirred for 1 h. The reaction mixture was cooled toroom temperature and dilute hydrochloric acid was added, which wasfollowed by extraction with chloroform. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. n-Hexane wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-n-hexane to give3-cyano-4-isobutylbenzoic acid (8.5 g), melting point: 118° C.

To tert-butyl alcohol containing 3-cyano-4-isobutylbenzoic acid (8.5 g)and triethylamine (4.2 g) was added diphenylphosphoryl azide (11.5 g) atroom temperature and the mixture was stirred at a refluxing temperaturefor 1 h. The solvent was evaporated under reduced pressure. To theresidue was added aqueous potassium carbonate solution and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, after which thesolvent was evaporated under reduced pressure. To the residue were added6N hydrochloric acid (10 ml) and methanol (100 ml) and the mixture wasstirred at a refluxing temperature for 1 h. The solvent was evaporatedunder reduced pressure. To the residue was added aqueous sodiumhydroxide solution and the mixture was extracted with toluene. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from a mixed solvent of diisopropylether-n-hexane to give the title compound (6.0 g), melting point: 68° C.

Starting Material Synthesis Example 52 5-Amino-2-hexyloxybenzonitrile

To dimethylformamide solution (91 ml) containing2-chloro-5-nitrobenzonitrile (18.2 g) and n-hexanol (11.2 g) was addedsodium hydride (60% content, 4.8 g) under ice-cooling and the mixturewas stirred for 1 h. The reaction mixture was added to water andextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (mobile phase: chloroform) to give2-n-hexyloxy-5-nitrobenzonitrile (16.2 g). Then, ammonium chloride (0.2g) and iron powder (1.6 g) were added to a mixed solvent of water (6.3ml) and ethanol (17 ml), and the mixture was heated to 65° C. Then, theobtained ethanol solution (4 ml) containing5-nitro-2-n-hexyloxybenzonitrile (16.2 g) was added dropwise thereto,and the mixture was stirred at a refluxing temperature for 30 min. Thereaction mixture was ice-cooled and filtrated and the solvent wasevaporated under reduced pressure. To the residue was added aqueoussodium hydroxide solution and the mixture was extracted with toluene.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, after which the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (mobile phase: chloroform) to give the title compound(6.0 g).

¹H-NMR(270 MHz, CDCl₃) δ(ppm):0.87–0.93(3H, m), 1.30–1.37(4H, m),1.43–1.51(2H, m), 1.78(2H, dt, J=6.6, 7.3 Hz), 4.03(2H, t, J=7.3 Hz),6.90(1H, d, J=9.2 Hz), 7.66(1H, dd, J=2.6, 9.2 Hz), 7.76(1H, d, J=2.6Hz)

Starting Material Synthesis Example 535-Amino-2-(2-(2-dimethylamino)ethoxy)benzonitrile

To dimethylformamide solution (30 ml) containing2-chloro-5-nitrobenzonitrile (20 g) and 2-dimethylaminoethanol (10.7 g)was added sodium hydride (60% content, 4.9 g) under ice-cooling, and themixture was stirred for 1 hr. The reaction mixture was added to waterand extracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (mobile phase: chloroform) to give2-(2-(2-dimethylamino)ethoxy)-5-nitrobenzonitrile (34.8 g). Then,ammonium chloride (9.3 g) and iron powder (35 g) were added to a mixedsolvent of water (130 ml) and ethanol (400 ml), and the mixture washeated to 65° C. Then, ethanol solution (20 ml) containing2-(2-(2-dimethylamino)ethoxy)-5-nitrobenzonitrile (34.8 g) was addeddropwise over 20 min and the mixture was stirred at a refluxingtemperature for 30 min. The reaction mixture was ice-cooled andfiltrated. The solvent was evaporated under reduced pressure. To theresidue was added aqueous sodium hydroxide solution and the mixture wasextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. Diisopropyl ether was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-n-hexane to give the titlecompound (20.1 g), melting point: 192–193° C.

Starting Material Synthesis Example 54 5-Amino-2-pheoxybenzonitrile

To a dimethylformamide solution (30 ml) containing2-chloro-5-nitrobenzonitrile (10 g) and phenol (5.7 g) was added sodiumhydride (60% content, 2.63 g) under ice-cooling, and the mixture wasstirred for 1 h. The reaction mixture was added to water and extractedwith toluene. The organic layer was washed saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. The residue was recrystallized from diisopropylether to give 5-nitro-2-phenoxybenzonitrile (10.8 g), melting point:126° C.

Subsequently, ammonium chloride (2.9 g) and iron powder (8.8 g) wereadded to mixed solvent of water (130 ml) and ethanol (120 ml), and themixture was heated to 65° C. Then, ethanol solution (20 ml) containing5-nitro-2-phenoxybenzonitrile (10.8 g) was added dropwise over 20 minand the mixture was stirred at a refluxing temperature for 30 min. Thereaction mixture was ice-cooled and filtrated. The solvent wasevaporated under reduced pressure. To the residue was added aqueoussodium hydroxide solution and the mixture was extracted with toluene.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, after which the solvent was evaporated underreduced pressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-n-hexane to give the title compound (3 g), meltingpoint: 89° C.

Starting Material Synthesis Example 555-Amino-2-cyclohexyloxybenzonitrile

To dimethylformamide solution (35 ml) containing2-chloro-5-nitrobenzonitrile (14.1 g) and cyclohexanol (8.5 g) was addedsodium hydride (60% content, 3.7 g) under ice-cooling, and the mixturewas stirred for 1 h. The reaction mixture was added to water andextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate, after which the solventwas evaporated under reduced pressure. The residue was recrystallizedfrom diisopropyl ether to give 2-cyclohexyloxy-5-nitrobenzonitrile (11.6g), melting point: 97–98° C.

Subsequently, ammonium chloride (1.8 g) and iron powder (9.2 g) wereadded to a mixed solvent of water (32 ml) and ethanol (130 ml), and themixture was heated to 65° C. Then, ethanol solution (4 ml) containing2-cyclohexyloxy-5-nitrobenzonitrile (11.6 g) was added dropwise over 20min and the mixture was stirred at a refluxing temperature for 30 min.The reaction mixture was ice-cooled and filtrated. The solvent wasevaporated under reduced pressure. To the residue was added aqueoussodium hydroxide solution and the mixture was extracted with toluene.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, after which the solvent was evaporated underreduced pressure. n-Hexane was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof diisopropyl ether-n-hexane to give the title compound (9.5 g),melting point: 59° C.

Starting Material Synthesis Example 565-Amino-2-[bis(2-hydroxyethyl)amino]benzonitrile

2-Chloro-5-nitrobenzonitrile (25.5 g) and silver nitrate (28.5 g) wereadded to diethanolamine (102 g) and the mixture was stirred at 100° C.for 1 h. The reaction mixture was cooled to room temperature and thesolid was filtered off. To the filtrate was added water and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, after which thesolvent was evaporated under reduced pressure. Diisopropyl ether wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous methanol to give2-bis(2-hydroxyethyl)amino-5-nitrobenzonitrile (21.2 g).

¹H-NMR(270 MHz, CDCl₃) δ(ppm):3.69(4H, q, J=5.3 Hz), 3.84 (4H, q, J=5.3Hz), 4.95 (2H, t, J=5.3 Hz), 7.15 (1H, d, J=9.4 Hz), 8.12 (1H, dd,J=2.6, 9.4 Hz), 8.36 (1H, d, J=2.6 Hz)

Subsequently, ammonium chloride (0.9 g) and iron powder (4.5 g) wereadded to a mixed solvent of water (10 ml) and ethanol (30 ml), and themixture was heated to 65° C. Then,2-bis(2-hydroxyethyl)amino-5-nitrobenzonitrile (11 g) was added in partsover 20 min and the mixture was stirred at a refluxing temperature for30 min. The reaction mixture was ice-cooled and filtrated. The solventwas evaporated under reduced pressure. To the residue was added aqueoussodium hydroxide ice solution and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. n-Hexane was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof diisopropyl ether-n-hexane to give the title compound (8 g), meltingpoint: 38° C.

Starting Material Synthesis Example 575-Amino-2-(2,2,2,-trifluoroethoxy)benzonitrile

To a dimethylformamide solution (30 ml) containing2-chloro-5-nitrobenzonitrile (10 g) and 2,2,2-trifluoroethanol (6 g) wasadded sodium hydride (60% content, 2.65 g) under ice-cooling, and themixture was stirred for 1 h. The reaction mixture was added to water andextracted with toluene. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. Diisopropyl ether wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of toluene-diisopropyl ether to give5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (9.4 g), melting point:94° C.

Subsequently, ammonium chloride (0.5 g) and iron powder (2.5 g) wereadded to a mixed solvent of water (40 ml) and ethanol (120 ml), and themixture was heated to 65° C. Then,5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (80.5 g) was added inparts over 20 min and the mixture was stirred at a refluxing temperaturefor 30 min. The reaction mixture was ice-cooled and filtrated. Thesolvent was evaporated under reduced pressure. To the residue was addedaqueous sodium hydroxide solution and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (70 g),melting point: 98–100° C.

Starting Material Synthesis Example 585-Amino-2-(4-tert-butyldimethylsilyloxypiperidino)benzonitrile

5-Amino-2-(4-hydroxypiperidino)benzonitrile (4.0 g),tert-butyldiethylsilyl chloride (3.0 g) and imidazole (1.6 g) werestirred in dimethylformamide (20 ml) at room temperature for 1 h. Thereaction mixture was treated with aqueous sodium hydrogen carbonatesolution and extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. The residue wasrecrystallized from n-hexane to give the title compound (4.2 g), meltingpoint: 88–90° C.

Starting Material Synthesis Example 592-[N-(3-Cyano-4-neopentyloxyphenyl) amino]ethyl acetate

To a dimethylformamide solution (50 ml) containingN-(3-cyano-4-neopentyloxyphenyl)-tert-butoxycarboxamide (5 g) was addedsodium hydride (60% content, 0.8 g) under ice-cooling, and the mixturewas stirred for 30 min under ice-cooling. The mixture was warmed to roomtemperature and stirred further for 1 h. Thereafter, the mixture wasice-cooled again and 2-bromoethyl acetate (2.6 g) was added, and themixture was stirred for 1 h. The reaction mixture was poured into waterand extracted with ethyl acetate. The extract was washed with 0.1 Nhydrochloric acid and saturated brine, and washed with anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:methylene chloride) to give2-[N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)]aminoethylacetate (3.5 g) as an oily substance. This oily substance was added totrifluoroacetic acid (7 ml) at room temperature and the mixture wasstirred for 1 h. The reaction mixture was poured into aqueous potassiumcarbonate solution and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated and the obtained residue was purified bysilica gel column chromatography (mobile phase: chloroform) to give thetitle compound (2.1 g) as an oily substance.

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.09(9H, s), 2.00(3H, s), 3.69(2H, s),3.81(2H, t, J=5.2 Hz), 4.20(2H, t, J=5.2 Hz), 6.99(1H, d, J=9.2 Hz),7.35–7.42(2H, m)

Starting Material Synthesis Example 605-Amino-2-(4-piperidinopiperidin-1-yl)benzonitrile

2-Chloro-5-nitrobenzonitrile (3.9 g) and piperidinopiperidine (7.2 g)were added to ethanol (40 ml), and the mixture was stirred at 78° C. for3 h. The solvent was evaporated under reduced pressure. The residue wastreated with aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from ethanol togive 5-nitro-2-(4-piperidinopiperidin-1-yl)benzonitrile (6.2 g), meltingpoint: 134–135° C.

Subsequently, ammonium chloride (0.7 g) and iron powder (3.8 g) wereadded to a mixed solvent of water (30 ml) and ethanol (120 ml), and themixture was heated to 65° C. Then,5-nitro-2-(4-piperidinopiperidin-1-yl)benzonitrile (6.2 g) was added inparts over 20 min and the mixture was stirred at a refluxing temperaturefor 30 min. The reaction mixture was ice-cooled and filtrated. Thesolvent was evaporated under reduced pressure. To the residue was addedaqueous sodium hydroxide solution and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (4.8 g),melting point: 110–112° C.

Starting Material Synthesis Example 611-(4-Amino-2-cyanophenyl)-4-piperidinyl benzoate

5-Nitro-2-(4-hydroxypiperidin-1-yl)benzonitrile (20 g) was dissolved inpyridine (100 ml). To the solution was added dropwise toluene solution(50 ml) containing benzoyl chloride (12.8 g) under ice-cooling, and themixture was stirred at room temperature for 3 h. The reaction mixturewas poured into water. The obtained crystals were recrystallized from amixed solvent of ethyl acetate-n-hexane to give1-(2-cyano-4-nitrophenyl)-4-piperidinyl benzoate (32.3 g), meltingpoint: 143–145° C.

Subsequently, ammonium chloride (3.4 g) and iron powder (18 g) wereadded to a mixed solvent of water (80 ml) and ethanol (240 ml), and themixture was heated to 65° C. Thereafter,1-(2-cyano-4-nitrophenyl)-4-piperidinyl benzoate (32.3 g) was added inparts over 20 min and the mixture was stirred at a refluxing temperaturefor 30 min. The reaction mixture was ice-cooled and filtrated. Thesolvent was evaporated under reduced pressure. To the residue was addedaqueous sodium hydroxide solution and the mixture was extracted withtoluene. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue toallow crystallization. The crystals were recrystallized from a mixedsolvent of ethyl acetate-n-hexane to give the title compound (25.3 g),melting point: 154–155° C.

Starting Material Synthesis Example 621-(4-Bromophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 4-bromophenylhydrazine was used insteadof 4-fluorophenylhydrazine, the title compound was obtained, meltingpoint: 213° C.

Starting Material Synthesis Example 631-(4-Iodophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 4-iodophenylhydrazine was used insteadof 4-fluorophenylhydrazine, the title compound was obtained, meltingpoint: 225° C.

Starting Material Synthesis Example 641-(4-Chlorophenyl)-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that 4-chlorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 217° C.

Starting Material Synthesis Example 651-(4-Bromophenyl)-3-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 15, except that 4-bromophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 226° C.

Starting Material Synthesis Example 661-(4-Chlorophenyl)pyrrole-3-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 34, except that 4-chloroaniline was used instead of4-fluoroaniline, the title compound was obtained, melting point:222–224° C.

Starting Material Synthesis Example 671-(3-Chlorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 3-chlorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 145° C.

Starting Material Synthesis Example 681-(3,4-Dichlorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 3,4-dichlorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 188° C.

Starting Material Synthesis Example 691-(3,4-Difluorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 3,4-difluorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 148° C.

Starting Material Synthesis Example 701-(3-Chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 3-chloro-4-fluorophenylhydrazine wasused instead of 4-fluorophenylhydrazine, the title compound wasobtained, melting point: 187° C.

Starting Material Synthesis Example 711-(4-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 4-trifluoromethylphenylhydrazine wasused instead of 4-fluorophenylhydrazine, the title compound wasobtained, melting point: 181° C.

Starting Material Synthesis Example 725-Amino-2-(4-morpholinopiperidin-1-yl)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 4-morpholinopiperidine synthesized accordingto Tetrahedron, vol. 38, No. 3, p. 413 (1982) instead of piperidine, thetitle compound was obtained, melting point: 84–86° C.

Starting Material Synthesis Example 735-Amino-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 4-(4-methylpiperazin-1-yl)piperidinesynthesized according to Tetrahedron, vol. 38, No. 3, p. 413 (1982)instead of piperidine, the title compound was obtained, melting point:174° C.

Starting Material Synthesis Example 74 5-Amino-2-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 4-[bis(2-hydroxyethyl)amino]piperidinesynthesized according to Tetrahedron, vol. 38, No. 3, p. 413 (1982)instead of piperidine, the title compound was obtained, melting point:45–47° C.

Starting Material Synthesis Example 755-Amino-2-[4-(dimethylamino)piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 4-dimethylaminopiperidine was usedinstead of piperidine, the title compound was obtained.

1H-NMR (400 MHz, CDCl₃) δ(ppm): 1.75 (2H, dd, J=3.3, 11.9 Hz), 1.90 (2H,d, J=12.5 Hz), 2.21–2.43 (1H, m), 2.31 (6H, s), 2.64–2.77 (2H, d, J=11.9Hz), 3.62 (2H, d, J=7.9 Hz), 6.81–6.95 (3H, m).

Starting Material Synthesis Example 76 5-Amino-2-pyrrolidinobenzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that pyrrolidine was used instead ofpiperidine, the title compound was obtained, melting point: 113° C.

Starting Material Synthesis Example 775-amino-2-homopiperidinobenzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that homopiperidine was used instead ofpiperidine, the title compound was obtained.

¹H-NMR (400M Hz, CDCl₃) δ(ppm): 1.55–1.70 (4H, m), 1.75–1.90 (4H, m),3.20 (2H, brs), 3.39 (4H, t, J=5.9 Hz), 6.7–6.9(3H, m)

Starting Material Synthesis Example 781-(2-chlorophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1, except that 2-chlorophenylhydrazine was usedinstead of 4-fluorophenylhydrazine, the title compound was obtained,melting point: 114° C.

Starting Material Synthesis Example 795-Amino-2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 4-[2-(2-hydroxyethoxy)ethyl]piperazine was used instead of piperidine, the title compound wasobtained.

¹H-NMR (270 MHz, CDCl₃)δ(ppm):2.66 (2H, d, J=5.3 Hz), 2.74 (2H, d, J=4.6Hz), 3.09 (4H, dd, J=4.6, 5.3 Hz), 3.62–3.71 (8H, m), 4.2–4.8 (2H, br),6.80–6.92 (3H, m)

Starting Material Synthesis Example 80 5-Amino-2-(1,4-dioxa-8-azaspiro[4,5]deca-8-yl) benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 1,4-dioxa-8-azaspiro[4,5]decane wasused instead of piperidine, the title compound was obtained, meltingpoint: 98° C.

Starting Material Synthesis Example 815-Amino-2-(1-benzylpiperidin-4-yloxy)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 36, except that 1-benzyl-4-hydroxypiperidine was usedinstead of neopentyl alcohol, the title compound was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃) δ(ppm):1.80–1.98 (5H, m), 2.33 (2H, m),2.70–2.85 (2H, m), 3.52 (2H, s), 3.59 (2H, brs), 4.29 (1H, m),6.81–6.83(7H, m)

Starting Material Synthesis Example 825-Amino-2-(4-phenylpiperidin-1-yl)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 4-phenylpiperidine was used instead ofpiperidine, the title compound was obtained, melting point: 158–162° C.

Starting Material Synthesis Example 835-Amino-2-[4-(4-chlorophenyl)piperazin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 4-(4-chlorophenyl)piperazine was usedinstead of piperidine, the title compound was obtained as an oil.

¹H-NMR (400 MHz, DMSO) δ(ppm):3.05 (4H, brs), 3.28 (4H, brs), 5.25 (2H,brs), 6.84 (2H, m), 7.01 (1H, brs), 7.01 (2H, d, J=7.8 Hz), 7.25 (2H, d,J=7.8 Hz)

Starting Material Synthesis Example 845-Amino-2-(4-thiomorpholinopiperidin-1-yl)benzonitrile

Reductive amination was conducted according to J. Org. Chem., vol. 55,p. 2552 (1990) using 5-nitro-2-(4-oxopiperidin-1-yl) benzonitrile andthiomorpholine. Then, the nitro group was reduced in the same manner asin Starting Material Synthesis Example 40 to give the title compound,melting point: 138° C.

Starting Material Synthesis Example 855-Amino-2-[4-[N-tert-butoxycarbonyl-N-(2-hydroxyethyl) amino]piperidin-1-yl]benzonitrile

(1) 5-Nitro-2-(4-oxopiperidin-1-yl) benzonitrile

2-Chloro-5-nitrobenzonitrile (15 g), 4-piperidone monohydratehydrochloride (13.9 g) and triethylamine (25 ml) were added toacetonitrile (100 ml), and the mixture was stirred at a refluxingtemperature for 1.5 h. 0.5 N Aqueous hydrochloric acid solution (200 ml)was added to the reaction mixture to allow crystallization to give thetitle compound (16.1 g), melting point: 109° C.

(2) 2-[4-(2-Hydroxyethylamino)piperidin-1-yl]-5-nitrobenzonitrile

5-Nitro-2-(4-oxopiperidin-1-yl)benzonitrile (5.0 g), 2-hydroxyethylamine(1.5 g) and sodium cyanoborohydride (1.3 g) were added to a mixedsolvent of methanol (100 ml) and tetrahydrofuran (50 ml) and the mixturewas stirred at room temperature for 1 h. An aqueous hydrochloric acidsolution was added to keep the reaction mixture acidic. The solvent wasevaporated under reduced pressure. Aqueous sodium hydroxide solution wasadded to the residue and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, after which the solvent was evaporated underreduced pressure. Diisopropyl ether was added to the residue to allowprecipitation, whereby the title compound (3.6 g) was obtained, meltingpoint: 115° C.

(3)2-[4-[N-tert-Butoxycarbonyl-N-(2-hydroxyethylamino)]piperidin-1-yl]-5-nitrobenzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 48 using2-[4-(2-hydroxyethylamino)piperidin-1-yl]-5-nitrobenzonitrile instead of5-nitro-2-homopiperazinebenzonitrile, the title compound was obtained,melting point: 88° C.

(4)5-Amino-2-[4-[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]piperidin-1-yl]benzonitrile

Reduction was conducted according to Starting Material Synthesis Example40 using2-[4-[N-tert-butoxycarbonyl-N-(2-hydroxyethylamino)]piperidin-1-yl]-5-nitrobenzonitrileto give the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.41 (9H, s), 1.5–1.7 (2H, m), 1.7–2.0(2H, m), 2.6–2.8 (2H, m), 3.0–3.5 (7H, m), 4.68 (1H, brs), 5.19 (2H, s),6.7–6.9 (2H, m), 6.96 (1H, d, J=9.8 Hz)

Starting Material Synthesis Example 865-Amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile

According to Tetrahedron vol. 38(3), p. 413 (1982), reductive amidationwas conducted using 5-nitro-2-piperazinebenzonitrile synthesized inStarting Material Synthesis Example 47 and2,3,5,6-tetrahydropyran-4-one, and reduction reaction was conducted inthe same manner as in Starting Material Synthesis Example 40 to give thetitle compound, melting point: 162° C.

¹H-NMR (400 MHz, DMSO-dl) δ(ppm):1.39–1.43 (2H, m), 1.71 (2H, d, J=11.7Hz), 2.38–2.50 (1H, m), 2.52–2.63 (4H, brs), 2.86–2.97 (4H, brs), 3.28(2H, dd, J 11.2, 11.7 Hz), 3.88 (2H, d, J=9.7 Hz), 5.19 (2H, brs), 6.81(2H, brs), 6.92–6.94 (1H, m)

Starting Material Synthesis Example 875-Amino-2-[4-(3,4,5,6-tetrahydro-2H-thiopyran-4-yl)piperazin-1-yl]benzonitrile

According to Tetrahedron vol. 38(3), p. 413 (1982), reductive amidationwas conducted using 5-nitro-2-piperazinebenzonitrile synthesized inStarting Material Synthesis Example 47 and2,3,5,6-tetrahydrothiopyran-4-one, and reduction reaction was conductedin the same manner as in Starting Material Synthesis Example 40 to givethe title compound, melting point: 109° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.60–1.76 (2H, m), 2.14 (2H, d, J=10.7Hz), 2.34–2.40 (1H, m), 2.64–2.73 (2H, m) 2.73–2.75 (4H, m), 0.03 (4H,m), 3.61 (2H, brs), 6.79–6.88 (3H, m)

Starting Material Synthesis Example 881-(4-Chlorophenyl)-5-ethylpyrazole-4-carboxylic chloride

A suspension of 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid(50 g) synthesized in Starting Material Synthesis Example 8, thionylchloride (17 ml), toluene (200 ml) and dimethylformamide (0.1 ml) wasrefluxed under heating for 3 h. After the reaction, the solvent wasevaporated to give the title compound (54 g), melting point: 105–107° C.

Starting Material Synthesis Example 895-Amino-2-[4-(N-2-hydroxyethyl-N-methylamino)piperidin-1-yl]benzonitrile

According to Tetrahedron, vol. 38, No. 3, p. 413 (1982) and using5-nitro-2-(4-oxopiperidino) benzonitrile and N-methylethanolamine,2-[4-(N-2-hydroxyethyl-N-methylamino)piperidin-1-yl]-5-nitrobenzonitrile was synthesized, which was subjectedto reduction according to Starting Material Synthesis Example 40 to givethe title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.55 (2H, m), 1.7–1.85 (2H, m),2.22 (3H, s), 2.35–2.5 (13H, m), 2.55–2.65 (2H, m), 3.15–3.25 (2H, m),3.35–3.5 (4H, m), 4.30 (1H, brs), 5.16 (2H, brs), 6.7–6.9 (2H, m), 6.93(1H, d, J=9.3 Hz)

Starting Material Synthesis Example 901-(4-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1 using 4-trifluoromethylphenylhydrazine (12.8 g) andethyl 2-ethoxymethyleneacetoacetate (12.3 g), the title compound (12.3g) was obtained, melting point: 181° C.

Starting Material Synthesis Example 915-Amino-2-[4-(4-tert-butoxycarbonylpiperazin-1-yl)piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 84, except that 1-tert-butoxycarbonylpiperazine wasused instead of thiomorpholine, the title compound was obtained, meltingpoint: 172° C.

Starting Material Synthesis Example 921-Benzyl-3-methylpyrazole-4-carboxylic acid and1-benzyl-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1 using benzylhydrazine dihydrochloride (8.0 g) andethyl 2-ethoxymethyleneacetoacetate (7.6 g), the residue wasrecrystallized from ethyl acetate to give1-benzyl-3-methylpyrazole-4-carboxylic acid (2.45 g).

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):2.29 (3H, s), 5.26 (2H, s), 7.2–7.4(5H, m), 8.26 (1H, s), 12.15 (1H, brs)

The mother liquor thereof was concentrated and recrystallized twice froma mixed solvent of ethyl acetate-diisopropyl ether to give1-benzyl-5-methylpyrazole-4-carboxylic acid (0.8 g).

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):2.45 (3H, s), 5.36 (2H, s), 7.13 (2H,d, J=7.3 Hz), 7.2–7.4 (3H, m), 7.78 (1H, s), 12.23 (1H, brs)

Starting Material Synthesis Example 933-Methyl-1-phenethylpyrazole-4-carboxylic acid and5-methyl-1-phenethylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1 using phenelzine (15 g) and ethyl2-ethoxymethyleneacetoacetate (12 g), the residue was recrystallizedfrom a mixed solvent of ethyl acetate-diisopropyl ether to give3-methyl-1-phenethylpyrazole-4-carboxylic acid (5.5 g).

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):2.31 (3H, s), 3.08 (2H, d, J=6.8 Hz),4.27 (2H, d, J c 6.8 Hz), 7.15–7.3 (5H, m), 7.99 (1H, s), 12.07 (1H,brs)

The mother liquor thereof was concentrated and hexane was added. Theinsoluble matter was filtrated and5-methyl-1-phenethylpyrazole-4-carboxylic acid (0.9 g) was obtained ascrystals from the filtrate.

¹H-NMR (400 MHz, DMSO-d₆) 8(pp):2.15 (3H, s), 3.04 (2H, d, J=6.8 Hz),4.27 (2H, d, J=6.8 Hz), 7.08 (2H, d, J=7.3 Hz), 7.15–7.3 (3H, m), 7.75(1H, s), 12.13 (1H, brs)

Starting Material Synthesis Example 945-Amino-2-[4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 85(2), (3) and (4) using5-nitro-2-(4-oxopiperidino)benzonitrile and 2-methoxyethylamine, thetitle compound as obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.41 (9H, s), 1.55–1.75 (2H, m),1.75–2.0 (2H, m), 2.6–2.75 (2H, m), 3.15–3.45 (7H, m), 3.26 (3H, s),5.19 (2H, s), 6.75–6.85 (2H, m), 6.92 (1H, d, J=9.2 Hz)

Starting Material Synthesis Example 955-Amino-2-[4-[N-(2-methoxyethyl)-N-methylamino]piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 84, except that 2-methoxyethylmethylamine was usedinstead of thiomorpholine, the title compound was obtained, meltingpoint: 88° C.

Starting Material Synthesis Example 965-Amino-2-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 84, except that bis(2-methoxyethyl)amine was usedinstead of thiomorpholine, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.45–1.6 (2H, m), 1.7–1.8 (2H, m),2.5–2.65 (3H, m), 2.65 (4H, t, J=6.3 Hz), 3.15–3.25 (2H, m), 3.24 (6H,s), 3.33 (4H, t, J=6.3 Hz), 5.17 (2H, s), 6.75–6.8 (2H, m), 6.93 (1H, d,J=9.7 Hz)

Starting Material Synthesis Example 975-Methyl-1-(2-pyridyl)pyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1 using 2-pyridylhydrazine (8.0 g) and ethyl2-ethoxymethyleneacetoacetate (13.7 g), the title compound (9.4 g) wasobtained, melting point: 165° C.

Starting Material Synthesis Example 985-Amino-2-[4-(4-hydroxypiperidino)piperidin-1-yl]benzonitrile

According to Tetrahedron vol. 38(3), p. 413 (1982), reductive amidationwas conducted using 5-nitro-2-(4-oxopiperidin-1-yl)benzonitrile and4-hydroxypiperazine, and reduction reaction was conducted in the samemanner as in Starting Material Synthesis Example 40 to give the titlecompound, melting point: 175° C.

Starting Material Synthesis Example 995-Amino-2-[4-(4-morpholinomethylpiperidino)]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 2-chloro-5-nitrobenzonitrile and4-morpholinomethylpiperidine, the title compound was obtained.

1H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.15–1.3 (2H, m), 1.55–1.65 (1H, m),1.75–1.85 (2H, m), 2.17 (2H, d, J=7.3 Hz), 2.25–2.4 (4H, m), 2.55–2.65(2H, m), 3.1–3.2 (2H, m), 3.57 (4H, t, J=4.4 Hz), 5.16 (2H, s),6.75–6.85 (2H, m), 6.93 (1H, d, J=9.3 Hz)

Starting Material Synthesis Example 1001-(4-Nitrophenyl)-5-methylpyrazole-4-carboxylic acid

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 1 using 4-nitrophenylhydrazine and ethyl2-ethoxymethyleneacetoacetate, the title compound was obtained, meltingpoint: 202° C.

Starting Material Synthesis Example 1013-Bromo-4-(4-morpholinopiperidin-1-yl)aniline

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 3-bromo-4-chloronitrobenzene and4-morpholinopiperidine, the title compound was obtained, melting point:215–217° C.

Starting Material Synthesis Example 1022-Amino-5-(4-morpholinopiperidin-1-yl)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 5-chloro-2-nitrobenzonitrile and4-morpholinopiperidine, the title compound was obtained, melting point:178–180° C.

Starting Material Synthesis Example 103N-(4-Chloro-3-nitrophenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide

1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.7 g) wasadded to a pyridine solution of 4-chloro-3-nitroaniline (1 g) and themixture was stirred at room temperature for 2 h. After the reaction,water was added and the precipitated solid was collected by filtrationto give the title compound (2.1 g), melting point:221–225° C.

Starting Material Synthesis Example 104N-(4-Chloro-3-nitrophenyl)-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide

1-(4-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid obtainedin Starting Material Synthesis Example 90 was converted to acid chlorideaccording to Starting Material Synthesis Example 88. The acid chloridewas reacted and treated in the same manner as in Starting MaterialSynthesis Example 103 to give the title compound, melting point:206–208° C.

Starting Material Synthesis Example 1053-Methyl-4-(4-morpholinopiperidin-1-yl)aniline

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 4-chloro-3-methylnitrobenzene and4-morpholinopiperidine, the title compound was obtained, melting point:199–200° C.

Starting Material Synthesis Example 1063-Chloro-4-(4-morpholinopiperidin-1-yl)aniline

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 3,4-dichloronitrobenzene and4-morpholinopiperidine, the title compound was obtained, melting point:220–223° C.

Starting Material Synthesis Example 1074-(4-Morpholinopiperidin-1-yl)-3-trifluoromethylaniline

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 4-chloro-3-trifluoromethylnitrobenzene and4-morpholinopiperidine, the title compound was obtained, melting point:118–120° C.

Starting Material Synthesis Example 1085-Amino-2-(4-methoxymethoxypiperidin-1-yl) benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 59 using N-(tert-butoxycarbonyl)-4-hydroxypiperidine,sodium hydride and methoxymethylchloride,N-(tert-butoxycarbonyl)-4-methoxymethoxypiperidine was obtained. Thiswas treated with trifluoroacetic acid-chloroform to give4-methoxymethoxypiperidine, which was subjected to the reaction andtreatment in the same manner as in Starting Material Synthesis Example40 using 4-fold equivalents of triethylamine to give the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.6–1.7 (2H, m), 1.9–2.0 (2H, m),2.7–2.8 (2H, m), 3.0–3.1 (2H, m), 3.27 (3H, s), 3.6–3.7 (1H, m), 4.65(2H, s), 5.18 (2H, s, NH2), 6.7–6.8 (2H, m), 6.96 (1H, d, J=9.3 Hz).

Starting Material Synthesis Example 1095-Amino-2-[4-(2-methoxyethoxy)piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 108 using N-(tert-butoxycarbonyl)-4-hydroxypiperidine,the title compound was obtained.

1H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.5–1.65 (2H, m), 1.9–2.0 (2H, m),2.65–2.75 (2H, m), 3.0–3.1 (2H, m), 3.26 (3H, s), 3.4–3.5 (3H, m),3.5–3.6 (2H, m), 5.18 (2H, s, NH2), 6.75–6.85 (2H, m), 6.95 (1H, d,J=9.3 Hz).

Starting Material Synthesis Example 1103,5-Dichloro-4-(4-morpholinopiperidin-1-yl)aniline

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40 using 3,4,5-trichloronitrobenzene and4-morpholinopiperidine, the title compound was obtained, melting point:144–146° C.

Starting Material Synthesis Example 1115-Amino-2-{4-(2-hydroxyethyl)piperidin-1-yl}benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 4-piperidineethanol was used insteadof piperidine, the title compound was obtained, melting point: 60–63° C.

Starting Material Synthesis Example 1125-Amino-2-[4-(2-methoxyethyl)piperazin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 1-(2-methoxyethyl)piperazine was usedinstead of piperidine, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):2.45–2.6 (6H, m), 2.85–2.95 (4H, m),3.24 (3H, s), 3.45 (2H, t, J=5.9 Hz), 5.20 (2H, s), 6.75–6.85 (2H, m),6.95 (1H, d, J=9.3 Hz).

Starting Material Synthesis Example 1135-Amino-2-[4-(4-methoxypiperidin-1-yl)piperidin-1-yl]benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 84, except that 4-methoxypiperidine was used insteadof thiomorpholine, the title compound was obtained, melting point:125–130° C.

Starting Material Synthesis Example 1145-Amino-2-(3-morpholinopropoxy)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 36, using 1-(3-hydroxypropyl)morpholine and2-chloro-5-nitrobenzonitrile, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm):1.8–1.9 (2H, m), 2.3–2.5 (6H, m),3.5–3.6 (4H, m), 3.95–4.05 (2H, m), 5.06 (2H, s), 6.78 (1H, d, J=2.9Hz), 6.84 (1H, dd, J=8.8, 2.9 Hz), 6.96 (1H, d, J=8.8 Hz)

Starting Material Synthesis Example 1155-Amino-2-(2-morpholinoethoxy)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 36 using 1-(2-hydroxyethyl)morpholine and2-chloro-5-nitrobenzonitrile, the title compound was obtained.

¹H-NMR (400 MHz, DMSO) δ(ppm):2.4–2.5 (4H, m), 2.6–2.7 (2H, m), 3.5–3.6(4H, m), 4.08 (2H, d, J=5.9 Hz), 5.08 (2H, s), 6.78 (1H, d, J=2.5 Hz),6.84 (1H, dd, J=8.8, 2.5 Hz), 6.98 (1H, d, J=8.8 Hz).

Starting Material Synthesis Example 1165-Amino-2-(4-morpholinopiperidin-1-ylmethyl)benzonitrile

A suspension of carbon tetrachloride (400 ml) containing2-methyl-5-nitrobenzonitrile (24 g), N-bromosuccinicimide (26.4 g) and2,2′-azobis(isobutyronitrile) (0.8 g) was stirred at a refluxingtemperature for 4 h. The reaction mixture was added into saturatedaqueous sodium thiosulfate solution under room temperature, washed withwater and saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure.Acetonitrile (50 ml) solution of the obtained2-bromomethyl-5-nitrobenzonitrile (5 g), 4-morpholinopiperidine (5.3 g)and diisopropylethylamine (8.0 g) was stirred at a refluxing temperaturefor 1 h. 4N Hydrochloric acid was added under ice-cooling to adjust thesolution to pH 2 and the solution was washed with chloroform. Thesolution was adjusted to pH 10 with a 30% aqueous potassium carbonatesolution and extracted with chloroform. The organic layer was washedwith water and saturated brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (mobilephase:chloroform-methanol) to give2-(4-morpholinopiperidin-1-ylmethyl)-5-nitrobenzonitrile (1.7 g). Usingthis compound, reduction was conducted acording to Starting MaterialSynthesis Example 40 to give the title compound, melting point: 162–165°C.

Starting Material Synthesis Example 1175-Amino-2-(3-hydroxypropylthio)benzonitrile

By the reaction and treatment in the same manner as in Starting MaterialSynthesis Example 40, except that 3-mercapto-1-propanol was used insteadof piperidine, the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):1.5–1.7 (2H, m), 2.84 (2H, t, J=6.8Hz), 3.45 (2H, q apparent, J=5.3 Hz), 4.50 (1H, t, J=5.3 Hz), 5.77 (2H,s), 7.60 (1H, dd, J=8.8, 2.4 Hz), 6.89 (1H, d, J=2.4 Hz), 7.32 (1H, d,J=8.8 Hz).

EXAMPLE 1N-(3-Cyano-4-neopentyloxyphenyl)-1,5-dimethylpyrazole-4-carboxamide

1,5-Dimethylpyrazole-4-carboxylic acid (10 g), 1-hydroxybenzotriazole(11.6 g) and 1-ethyl-3-(3′dimethylaminopropyl)carbodiimide (16.3 g) wereadded to dimethylformamide (200 ml) and the mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was treated with aqueouspotassium carbonate solution. The organic layer was extracted with ethylacetate, washed with saturated brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from ethyl acetate to give 1-benzotriazole1,5-dimethylpyrazole-4-carboxylate (11.8 g), melting point 167–168° C.

1-Benzotriazole 1,5-dimethylpyrazole-4-carboxylate (3 g) and5-amino-2-neopentyloxybenzonitrile (2.4 g) were added to ethanol (30 ml)and the mixture was stirred at 78° C. for 3 h. After evaporation of thesolvent, the residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=50:1) to give the title compound (2.56g), melting point: 187–188° C.

EXAMPLE 2N-(3-Cyano-4-isobutoxyphenyl)-1,5-dimethylpyrazole-4-carboxamide

1-Hydroxybenzotriazole 1,5-dimethylpyrazole-4-carboxylate (2 g) and5-amino-2-isobutoxybenzonitrile (1.9 g) were added to ethanol (25 ml)and the mixture was stirred at 78° C. for 3 h. After evaporation of thesolvent, the residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=50:1) to give the title compound (0.8g), melting point: 160–162° C.

EXAMPLE 3N-(3-Cyano-4-piperidinophenyl)-1,5-dimethylpyrazole-4-carboxamide

1-Hydroxybenzotriazole 1,5-dimethylpyrazole-4-carboxylate (1.2 g) and5-amino-2-piperidinobenzonitrile (0.9 g) were added to ethanol (20 ml)and the mixture was stirred at 78° C. for 3 h. After evaporation of thesolvent, aqueous potassium carbonate solution was added to the residueand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. n-Hexanewas added to the residue to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give the title compound (0.7 g),melting point: 217–218° C.

EXAMPLE 4N-(3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1,5-dimethylpyrazole-4-carboxamide

1-Benzotriazole 1,5-dimethylpyrazole-4-carboxylate (3 g) and5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.9 g) wereadded to ethanol (25 ml) and the mixture was stirred at 78° C. for 3 h.After evaporation of the solvent, aqueous potassium carbonate solutionwas added to the residue and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. n-Hexane was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (0.65 g), melting point: 228–230° C.

EXAMPLE 5N-[3-Cyano-(4-hydroxypiperidin-1-yl)phenyl]-1,5-dimethylpyrazole-4-carboxamide

1-Benzotriazole 1,5-dimethylpyrazole-4-carboxylate (3 g) and5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (2.5 g) were added toethanol (35 ml) and the mixture was stirred at 78° C. for 3 h. Afterevaporation of the solvent, aqueous potassium carbonate solution wasadded to the residue and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. n-Hexane was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (0.9 g), melting point: 261–262° C.

EXAMPLE 6 4-(1-[2-Cyano-4-(1,5-dimethyl-4-pyrazolecarboxamide)phenyl]piperidine-4-yloxy)-4-oxobutyric acid

N-[3-Cyano-(4-hydroxypiperidin-1-yl)phenyl]-1,5-dimethylpyrazole-4-carboxamide(0.7 g), succinic anhydride (0.2 g) and a catalytic amount ofp-toluenesulfonic acid monohydrate were added to nitrobenzene (5 ml),and the mixture was reacted at 120° C. for 3 h. After cooling to roantemperature, diisopropyl ether was added and the precipitated crystalswere recrystallized from hydrous dimethylformamide to give the titlecompound (0.5 g), melting point: 211–212° C.

EXAMPLE 7N-(3-Cyano-4-n-hexyloxyphenyl)-1,5-dimethylpyrazole-4-carboxamide

1-Benzotriazole 1,5-dimethylpyrazole-4-carboxylate (1 g) and5-amino-2-n-hexyloxybenzonitrile (0.8 g) were added to ethanol (10 ml)and the mixture was stirred at 78° C. for 3 h. After evaporation of thesolvent, aqueous potassium carbonate solution was added to the residueand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. n-Hexanewas added to the residue to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give the title compound (0.7 g),melting point: 150–151° C.

EXAMPLE 8N-(3-Cyano-4-neopentyloxyphenyl)-1,3-dimethylpyrazole-4-carboxamide

1,3-Dimethylpyrazole-4-carboxylic acid (0.6 g),5-amino-2-neopentyloxybenzonitrile (0.9 g), triethylamine (1.0 g) anddiethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (0.5 g), melting point: 193–194° C.

EXAMPLE 9N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.2 g),5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.7 g) anddiethyl cyanophosphate (1.3 g) were added to dimethylformamide (10 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from a mixed solvent of ethylacetate-n-hexane to give the title compound (0.4 g), melting point:181–182° C.

EXAMPLE 10N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide½ hydrate

1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.1 g),5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.7 g) anddiethyl cyanophosphate (1.3 g) were added to dimethylformamide (10 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous ethanol to give the titlecompound (0.2 g), melting point: 126–127° C.

EXAMPLE 11N-(3-Cyano-4-isobutoxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (0.6 g),5-amino-2-isobutoxybenzonitrile (0.5 g), triethylamine (0.8 g) anddiethyl cyanophosphate (0.7 g) were added to dimethylformamide (8 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous ethanol to give the titlecompound (0.2 g), melting point: 179–180° C.

EXAMPLE 12N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3,5-dimethylpyrazole-4-carboxylic acid (2 g),5-amino-2-neopentyloxybenzonitrile (1.7 g), triethylamine (1.7 g) anddiethyl cyanophosphate (1.4 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (0.6 g), melting point: 174–175° C.

EXAMPLE 13N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrazole-4-carboxamide

1-(4-Fluorophenyl)pyrazole-4-carboxylic acid (2 g),5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (2 g) anddiethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (1.2 g), melting point: 196–197° C.

EXAMPLE 14N-(3-Cyano-4-neopentyloxyphenyl)-1(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide

1-(3-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (2 g),5-amino-2-neopentyloxybenzonitrile (1.8 g), triethylamine (1.6 g) anddiethyl cyanophosphate (1.4 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous ethanol to give the titlecompound (1.4 g), melting point: 116–118° C.

EXAMPLE 15N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrrole-3-carboxamide

1-(4-Fluorophenyl)pyrrole-3-carboxylic acid (2 g),5-amino-2-neopentyloxybenzonitrile (1.8 g), triethylamine (1.7 g) anddiethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (0.7 g), melting point: 167–169° C.

EXAMPLE 16N-(3-Cyano-4-isobutoxyphenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g),5-amino-2-isobutoxybenzonitrile (1.7 g), triethylamine (2.7 g) anddiethyl cyanophosphate (2.2 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-n-hexane to give the title compound (1.2 g), meltingpoint: 177–178° C.

EXAMPLE 17N-(3-Cyano-4-isobutoxyphenyl)-1-(4-fluorophenyl)-5-hydroxypyrazole-4-carboxamide

Ethyl 1-(4-fluorophenyl)-5-hydroxypyrazole-4-carboxylate (1 g) and5-amino-2-isobutoxybenzonitrile (0.8 g) were added to pyridine (10 ml)and the mixture was stirred at 120° C. for 4 h. After evaporation of thesolvent under reduced pressure, hydrochloric acid was added to theresidue and the mixture was extracted with chloroform. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from a mixed solvent of ethanol-diisopropylether to give the title compound (0.2 g), melting point: 207–208° C.

EXAMPLE 18N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-N,3-dimethylpyrazole-4-carboxamide½ hydrate

To dimethylformamide (5 ml) solution containingN-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide(1.5 g) was added sodium hydride (60% content, 0.2 g) under ice-coolingand the mixture was stirred for 1 h. A solution of dimethylformamide (1ml) containing methyl iodide (0.6 g) was added and the mixture wasstirred under ice-cooling for 1 h. The mixture was allowed to warm toroom temperature and stirred for 1 h. The reaction mixture was addedinto water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (mobile phase:ethyl acetate:n-hexane=5:1) to give the title compound (0.5 g), meltingpoint: 65–69° C.

EXAMPLE 19N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

Dichloroethane solution (45 ml) containing1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylic acid (8.1 g) andthionyl chloride (5.3 g) was stirred at 83° C. for 30 min to give acidchloride. This was added to pyridine solution (80 ml) containing ethylN-(3-cyano-4-neopentyloxyphenyl)glycine (5.3 g) under ice-cooling andthe mixture was stirred for 1 h. The reaction mixture was added intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, after which the solvent was evaporated underreduced pressure. Sodium hydroxide (1.8 g), water (40 ml) and ethanol(40 ml) were added to the residue and the mixture was stirred at arefluxing temperature for 1 h. The solvent was evaporated under reducedpressure. Dilute hydrochloric acid was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. n-Hexane was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of toluene-n-hexane to give the title compound (4.7g), melting point: 156.7° C.

EXAMPLE 20N-(3-Cyano-4-neopentyloxyphenyl)-1-phenyl-3-methylpyrazole-4-carboxamide

1-Phenyl-3-methylpyrazole-4-carboxylic acid (2.2 g),5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.3 g) anddiethyl cyanophosphate (2.7 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (2.4 g), melting point: 155–156° C.

EXAMPLE 21N-(3-Cyano-4-neopentyloxyphenyl)-1-methyl-3-phenylpyrazole-5-carboxamide

1-Methyl-3-phenylpyrazole-5-carboxylic acid (0.8 g),5-amino-2-neopentyloxybenzonitrile (0.8 g), triethylamine (1.2 g) anddiethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (0.3 g), melting point: 223–224° C.

EXAMPLE 22N-(3-Cyano-4-neopentyloxyphenyl)-1-methyl-5-phenylpyrazole-3-carboxamide

1-Methyl-5-phenylpyrazole-3-carboxylic acid (2.1 g),5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.4 g) anddiethyl cyanophosphate (2.7 g) were added to dimethylformamide (25 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous dimethylformamide to givethe title compound (3.1 g), melting point: 156–157° C.

EXAMPLE 23N-(3-Bromo-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.7 g),3-bromo-4-neopentyloxyaniline (2 g), triethylamine (2.3 g) and diethylcyanophosphate (1.9 g) were added to dimethylformamide (20 ml) and themixture was stirred at room temperature for 1 h. The reaction mixturewas added into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.n-Hexane was added to the residue to allow crystallization. The crystalswere recrystallized from hydrous dimethylformamide to give the titlecompound (1.4 g), melting point: 193–194° C.

EXAMPLE 24N-(3-Cyano-4-n-hexyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.0 g),5-amino-2-n-hexyloxybenzonitrile (1.0 g), triethylamine (1.4 g) anddiethyl cyanophosphate (1.2 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from ethyl acetate to give the titlecompound (0.5 g), melting point: 160–161° C.

EXAMPLE 255-Chloro-N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrazole-4-carboxamide

5-Chloro-1-(4-fluorophenyl)-3-pyrazole-4-carboxylic acid (1.0 g),5-amino-2-neopentyloxybenzonitrile (0.9 g), triethylamine (1.3 g) anddiethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml)and the mixture was stirred at roan temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. n-Hexane was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (0.6 g), melting point: 149–150° C.

EXAMPLE 26N-(3-Cyano-4-neopentyloxyphenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

1-(2,2,2-Trifluoroethyl)pyrazole-4-carboxylic acid (2.2 g),5-amino-2-neopentyloxybenzonitrile (2.5 g), 1-hydroxybenzotriazole (1.8g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.6 g) were addedto dimethylformamide (20 ml) and the mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from ethyl acetate togive the title compound (1.8 g), melting point 159–160° C.

EXAMPLE 27N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-5-methylpyrazole-3-carboxamide

1-(4-Fluorophenyl)-5-methylpyrazole-3-carboxylic acid (2.1 g),5-amino-2-neopentyloxybenzonitrile (2.0 g), triethylamine (2.9 g) anddiethyl cyanophosphate (2.3 g) were added to dimethylformamide (25 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Methanol was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (1.9 g), melting point: 146–147° C.

EXAMPLE 28N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-5-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-5-carboxylic acid (1.4 g),5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.9 g) anddiethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Methanol was added to the residue to allow crystallization.The crystals were recrystallized from hydrous methanol to give the titlecompound (0.3 g), melting point: 165° C.

EXAMPLE 29N-(3-Cyano-4-isobutylphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.5 g),5-amino-2-isobutylbenzonitrile (1.2 g), triethylamine (2.0 g) anddiethyl cyanophosphate (1.2 g) were added to dimethylformamide (15 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. A mixed solvent of ethyl acetate-n-hexane was added to theresidue to allow crystallization. The crystals were recrystallized fromhydrous dimethylformamide to give the title compound (0.9 g), meltingpoint: 178–179° C.

EXAMPLE 301-tert-Butyl-N-(3-cyano-4-neopentyloxyphenyl)-5-methylpyrazole-4-carboxamide

1-tert-Butyl-5-methylpyrazole-4-carboxylic acid (2 g),5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.3 g) anddiethyl cyanophosphate (2.7 g) were added to dimethylformamide (20 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Methanol was added to the residue to allow crystallization.The crystals were recrystallized from hydrous dimethylformamide to givethe title compound (2.2 g), melting point: 143–144° C.

EXAMPLE 31N-{3-Cyano-4-(2-(dimethylamino)ethoxy)phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamidehydrochloride ¼ hydrate

1-(4-Fluorophenyl)-5-dimethylpyrazole-4-carboxylic acid (35 g),1-hydroxybenzotriazole (25.5 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (36 g) were added to dimethylformamide (360 ml) and themixture was stirred at roan temperature for 1.5 h. The reaction mixturewas treated with aqueous potassium carbonate solution and extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, after which the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized fromethyl acetate to give 1-benzotriazole1-(4-fluorophenyl)-5-dimethylpyrazole-4-carboxylate (62 g), meltingpoint 166–168° C.

1-Benzotriazole 1-(4-fluorophenyl)-5-dimethylpyrazole-4-carboxylate (3g) and 5-amino-2-(2-(dimethylamino)ethoxy)benzonitrile (2.3 g) wereadded to ethanol (30 ml) and the mixture was stirred at 78° C. for 3 h.The solvent was evaporated and the residue was purified by silica gelcolumn chromatography (mobile phase:chloroform:methanol=50:1). To theobtained oily substance was added 10% hydrogen chloride-isopropanolsolution to allow crystallization and the crystals were recrystallizedfrom a mixed solvent of methanol-ethyl acetate to give the titlecompound (0.4 g), melting point: 258° C.

EXAMPLE 32N-(3-Cyano-4-neopentyloxyphenyl)-1-cyclohexyl-5-methylpyrazole-4-carboxamide1 hydrate

1-Cyclohexyl-5-methylpyrazole-4-carboxylic acid (1.2 g),5-amino-2-neopentyloxybenzonitrile (1.1 g), triethylamine (1.7 g) anddiethyl cyanophosphate (1.4 g) were added to dimethylformamide (15 ml)and the mixture was stirred at room temperature for 1 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Methanol was added to the residue to allow crystallization.The crystals were recrystallized from hydrous dimethylformamide to givethe title compound (1.2 g), melting point: 126–128° C.

EXAMPLE 33N-[3-Cyano-4-phenoxyphenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-Benzotriazole 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (1.6g) and 5-amino-2-phenoxybenzonitrile (1 g) were added to ethanol (12 ml)and the mixture was stirred at 78° C. for 3 h. The solvent wasevaporated and the residue was purified by silica gel columnchromatography (mobile phase:chloroform:methanol=50:1) andrecrystallized from ethyl acetate to give the title compound (0.7 g),melting point: 182–183° C.

EXAMPLE 34N-[3-Cyano-4-(2,2,2-trifluoroethoxy)phenyl-1-(4-fluorophenyl)pyrrole-3-carboxamide

Dichloroethane solution (10 ml) containing1-(4-fluorophenyl)pyrrole-3-carboxylic acid (1 g) and thionyl chloride(0.7 g) was stirred at 83° C. for 30 min to give acid chloride. This wasadded to pyridine solution (10 ml) containing5-amino-2-(2,2,2-trifluoroethoxy) benzonitrile (1.1 g) under ice-coolingand the mixture was stirred for 1 h. The reaction mixture was added intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine and the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof toluene-acetonitrile to give the title compound (0.4 g), meltingpoint: 227–228° C.

EXAMPLE 35N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)pyrrole-3-ylcarbonyl]glycine

To dimethylformamide solution (24 ml) containingN-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrrole-3-carboxamide(2.2 g) was added sodium hydride (60% content, 0.3 g) under ice-coolingand the mixture was stirred for 1 h. Dimethylformamide solution (1 ml)containing ethyl bromoacetate (1.2 g) was added and the mixture wasstirred for 1 h under ice-cooling, and after being warmed to roomtemperature, stirred for another 1 h. The reaction mixture was addedinto water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (mobile phase:ethyl acetate:n-hexane=5:1) to give ethylN-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)pyrrole-3-ylcarbonyl]glycineethyl as an oily sybstance. This was added to ethanol (10 ml) and 10%aqueous sodium hydroxide solution (10 ml) was added. The mixture wasstirred for 30 min at a refluxing temperature. The solvent wasevaporated under reduced pressure and dilute hydrochloric acid wasadded. The resulting crystals were recrystallized from hydrousdimethylformamide to give the title compound (0.8 g), melting point:248–249° C.

EXAMPLE 36N-(3-Cyano-4-cyclohexyloxyphenyl)-1-(4-fluorophenyl)pyrrole-3-carboxamide

1-(4-Fluorophenyl)pyrrole-3-carboxylic acid (1.5 g) and thionyl chloride(1.0 g) were reacted in dichloroethane (10 ml) at 110° C. for 30 min togive acid chloride. The solvent was evaporated under reduced pressure.To the residue were added 5-amino-2-cyclohexyloxybenzonitrile (1.6 g)and pyridine (10 ml) and the mixture was stirred at room temperature for1 h. The reaction mixture was treated with dilute hydrochloric acid andextracted with ethyl acetate. The organic layer was washed with sodiumhydrogen carbonate and saturated brine, and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Hydrous methanol was added to the residue to allowcrystallization. The crystals were further recrystallized from hydrousmethanol to give the title compound (1.9 g), melting point: 111–113° C.

EXAMPLE 37N-(3-Cyano-4-piperidinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-Benzotriazole 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (2 g)and 5-amino-2-piperidinobenzonitrile (1.1 g) were reacted at 78° C. for3 h in ethanol (20 ml). After evaporation of the solvent, aqueouspotassium carbonate solution was added to the residue and the mixturewas extracted with ethyl acetate. The organic layer was washed withdilute hydrochloric acid and saturated brine, and dried over anhydroussodium sulfate, after which the solvent was evaporated. A mixed solventof ethyl acetate-n-hexane was added to the residue to allowcrystallization. The crystals were recrystallized from ethyl acetate togive the title compound (1.2 g), melting point: 196–197° C.

EXAMPLE 38N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-5-methylpyrazol-4-ylcarbonyl]glycine

N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(1.8 g) and sodium hydride (60% content, 0.2 g) were reacted for 1 h indimethylformamide (24 ml) under ice-cooling. Dimethylformamide solution(1 ml) containing ethyl bromoacetate (0.8 g) was added and the mixturewas stirred for 1 h under ice-cooling and, after allowed to warm to roomtemperature, stirred for another 1 h. The reaction mixture was addedinto water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (mobilephase:ethyl acetate:n-hexane=5:1) to give ethylN-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-5-methylpyrazol-4-ylcarbonyl]glycineas an oily substance. This was added to ethanol (10 ml) and 10% aqueoussodium hydroxide solution (10 ml) was added. The mixture was stirred ata refluxing temperature for 30 min. The solvent was evaporated underreduced pressure. To the residue was added dilute hydrochloric acid andthe mixture was extracted with ethyl acetate, washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under reduced pressure. A mixed solvent oftoluene-n-hexane was added to the residue to allow crystallization. Thecrystals were recrystallized from a mixed solvent of toluene-n-hexane togive the title compound (0.7 g), melting point: 105–110° C.

EXAMPLE 39N-(3-Cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-5-methoxypyrazole-4-carboxamide

To a methanol solution (20 ml) containing metallic sodium (0.065 g) wereadded5-chloro-N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrazole-4-carboxamide(1 g) and a catalytic amount of potassium iodide, and the mixture wasstirred at 65° C. for 5 h. The solvent was evaporated. Water was addedto the residue to allow crystallization. The crystals wererecrystallized from hydrous methanol to give the title compound (0.3 g),melting point: 120–123° C.

EXAMPLE 40N-(3-Cyano-4-morpholinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.2 g) andthionyl chloride (1.5 g) was stirred at 83° C. for 30 min to give acidchloride. To this was added pyridine solution (10 ml) containing5-amino-2-morpholinobenzonitrile (2.0 g) under ice-cooling and themixture was stirred for 1 h. The reaction mixture was added into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, and the solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous ethanol to give the titlecompound (2.1 g), melting point: 201–202° C.

EXAMPLE 41N-(3-Cyano-4-diethylaminophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.2 g) andthionyl chloride (1.5 g) was stirred at 83° C. for 30 min to give acidchloride. To this was added pyridine solution (10 ml) containing5-amino-2-diethylaminobenzonitrile (1.9 g) under ice-cooling and themixture was stirred for 1 h. The reaction mixture was added into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, and the solvent was evaporated under reduced pressure.Diisopropyl ether was added to the residue to allow crystallization. Thecrystals were recrystallized from hydrous methanol to give the titlecompound (2.1 g), melting point: 135–136° C.

EXAMPLE 42N-[3-Cyano-4-(4-methylpiperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.2 g) andthionyl chloride (1.5 g) was stirred at 83° C. for 30 min to give acidchloride. To this was added pyridine solution (10 ml) containing5-amino-2-(4-methylpiperazin-1-yl)benzonitrile (1.9 g) under ice-coolingand the mixture was stirred for 1 h. The reaction mixture was treatedwith aqueous sodium hydroxide solution and extracted with ethyl acetate.The organic layer was washed with saturated brine, and the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized fromethanol to give the title compound (1.6 g), melting point: 205–207° C.

EXAMPLE 43N-(3-Cyano-4-piperidinophenyl)-1-(4-fluorophenyl)pyrrole-2-carboxamide

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)pyrrole-2-carboxylic acid (2 g) and thionyl chloride(1.4 g) was stirred at 83° C. for 30 min to give acid chloride. To thiswas added pyridine solution (20 ml) containing5-amino-2-piperidinobenzonitrile (2.0 g) under ice-cooling and themixture was stirred for 1 h. The reaction mixture was treated withaqueous sodium hydroxide solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-toluene to give the title compound (0.7g), melting point: 158–159° C.

EXAMPLE 44N-(3-Cyano-4-neopentyloxyphenyl)-5-methylpyrazole-4-carboxamide

5-Methylpyrazole-4-carboxylic acid (2 g),5-amino-2-neopentyloxybenzonitrile (3.2 g), 1-hydroxybenzotriazole (2.5g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.6 g) were addedto dimethylformamide (110 ml) and the mixture was stirred at roomtemperature for 5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=100:1), and the obtained oilysubstance was recrystallized from a mixed solvent of toluene-n-hexane togive the title compound (0.8 g), melting point: 133–134° C.

EXAMPLE 45N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-Benzotriazole 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (2 g)and 5-amino-2-(4-hydroxypiperidino) benzonitrile (1.0 g) were reacted inethanol (20 ml) at 78° C. for 3 h. After the evaporation of the solvent,aqueous potassium carbonate solution was added to the residue and themixture was extracted with ethyl acetate. The organic layer was washedwith dilute hydrochloric acid and saturated brine, and dried overanhydrous sodium sulfate, after which the solvent was evaporated.Diisopropanol was added to the residue to allow crystallization. Thecrystals were recrystallized from a mixed solvent of ethylacetate-toluene to give the title compound (0.7 g), melting point:215–216° C.

EXAMPLE 46N-(3-Cyano-4-neopentyloxyphenyl)-1-(2-hydroxyethyl)-5-methylpyrazole-4-carboxamide

1-(2-Hydroxyethyl)-5-methylpyrazole-4-carboxylic acid (1.7 g),5-amino-2-neopentyloxybenzonitrile (2.1 g), 1-hydroxybenzotriazole (1.6g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.3 g) were addedto dimethylformamide (20 ml) and the mixture was stirred at roomtemperature for 5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=100:1). Diisopropyl ether was added tothe obtained oily substance to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-diisopropyl etherto give the title compound (1.1 g), melting point: 98–100° C.

EXAMPLE 47 EthylN-(3-Cyano-4-piperidinophenyl)-N-[1-(4-fluorophenyl)pyrrol-2-ylcarbonyl]glycine

N-(3-Cyano-4-piperidinophenyl)-1-(4-fluorophenyl)pyrrol-2-ylcarboxamide(1.1 g) and sodium hydride (60% content, 0.2 g) were reacted indimethylformamide (24 ml) under ice-cooling for 1 h. Dimethylformamidesolution (1 ml) containing ethyl bromoacetate (0.8 g) was added and themixture was stirred under ice-cooling for 1 h and, after allowed to warmto room temperature, stirred for another 1 h. The reaction mixture wasadded into water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. A mixedsolvent of toluene-diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-n-hexane to give the title compound (1.3 g), meltingpoint: 138–139° C.

EXAMPLE 48N-(3-Cyano-4-piperidinophenyl)-N-[1-(4-fluorophenyl)pyrrol-2-ylcarbonyl]glycine1 hydrate

EthylN-(3-cyano-4-piperidinophenyl)-N-[1-(4-fluorophenyl)pyrrol-2-ylcarbonyl]glycine(1.0 g) was added to ethanol (10 ml), and 10% aqueous sodium hydroxidesolution (10 ml) was added. The mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure. Dilute hydrochloric acid was added to the residue and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof toluene-diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous methanolto give the title compound (0.5 g), melting point: 117–120° C.

EXAMPLE 49N-(3-Cyano-4-piperidinophenyl)-1-(4-fluorophenyl)pyrrole-3-carboxamide

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)pyrrole-3-carboxylic acid (2 g) and thionyl chloride(1.4 g) was stirred at 83° C. for 30 min to give acid chloride. To thiswas added pyridine solution (20 ml) containing5-amino-2-piperidinobenzonitrile (2.0 g) under ice-cooling and themixture was stirred for 1 h. The reaction mixture was treated withaqueous sodium hydroxide solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-n-hexane to give the title compound(0.7 g), melting point: 195–196° C.

EXAMPLE 50N-[3-Cyano-4-neopentyloxyphenyl]-1-(4-fluorophenyl)pyrrole-2-carboxamide

Dichloroethane solution (50 ml) containing1-(4-fluorophenyl)pyrrole-2-carboxylic acid (5 g) and thionyl chloride(3.5 g) was stirred at 83° C. for 1 h to give acid chloride. To this wasadded pyridine solution (50 ml) containing5-amino-2-neopentyloxybenzonitrile (5 g) under ice-cooling and themixture was stirred for 1 h. The reaction mixture was treated withaqueous sodium hydroxide solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of toluene-ethyl acetate to give the title compound (7.9g), melting point: 181–182° C.

EXAMPLE 51 Ethyl4-[N-(3-cyano-4-neopentyloxyphenyl)carbamoyl]-3-methylpyrazol-1-ylacetate

N-(3-Cyano-4-neopentyloxyphenyl)-5-methylpyrazole-4-carboxamide (2.4 g),potassium carbonate (1.1 g), potassium iodide (1.4 g) and ethylbromoacetate (1.4 g) were added to a mixed solvent of dimethylformamide(24 ml) and toluene (24 ml) and the mixture was stirred at 60° C. for 4h. The reaction mixture was added into water, washed with dilutehydrochloric acid and saturated brine, and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase: chloroform). Methylene chloride was added to the obtainedoily substance to allow crystallization. The crystals wererecrystallized from a mixed solvent of methylene chloride-n-hexane togive the title compound (0.7 g), melting point: 240° C.

EXAMPLE 524-[N-(3-Cyano-4-neopentyloxyphenyl)carbamoyl]-3-methylpyrazol-1-ylaceticacid

Ethyl4-[N-(3-cyano-4-neopentyloxyphenyl)carbamoyl]-3-methylpyrazol-1-ylacetate(0.7 g) was added to ethanol (5 ml) and 10% aqueous sodium hydroxidesolution (5 ml) was added. The mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure. To the residue was added dilute hydrochloric acid and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. Diisopropylether was added to the residue to allow crystallization. The crystalswere recrystallized from a mixed solvent of ethyl acetate-diisopropylether to give the title compound (0.2 g), melting point: 234–245° C.

EXAMPLE 53N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)pyrrol-2-ylcarbonyl]glycine½ hydrate

N-[3-Cyano-4-neopentyloxyphenyl]-1-(4-fluorophenyl)pyrrole-2-carboxamide (4.0 g) and sodium hydride (60% content, 0.6 g)were reacted in dimethylformamide (40 ml) under ice-cooling for 1 h.Dimethylformamide solution (3 ml) containing ethyl bromoacetate (3.4g)was added and the mixture was stirred under ice-cooling for 1 h, andafter allowed to warm to room temperature, stirred for another 1 h. Thereaction mixture was added into water and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. To the residue were added ethanol (40 ml) andthen 10% aqueous sodium hydroxide solution (50 ml). The mixture wasstirred at a refluxing temperature for 30 min. The solvent wasevaporated under reduced pressure. Dilute hydrochloric acid was added tothe residue and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. A mixed solvent of chloroform-n-hexane was added to theresidue to allow crystallization. The crystals were recrystallized fromhydrous ethanol to give the title compound (3.0 g), melting point:140–143° C.

EXAMPLE 54N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.0 g),5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (1.0 g),1-hydroxybenzotriazole (0.7 g) and1-ethyl-3-(3′dimethylaminopropyl)carbodiimide (1.0 g) were added todimethylformamide (20 ml) and the mixture was stirred at roomtemperature for 5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=100:1). Diisopropyl ether was added tothe obtained oily substance to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-diisopropyl etherto give the title compound (0.7 g), melting point: 224–225° C.

EXAMPLE 55N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.4 g) andthionyl chloride (1.6 g) was stirred at 83° C. for 30 min to give acidchloride. To this were added5-amino-2-(4-tert-butyldimethylsilyloxypiperidin-1-yl)benzonitrile (3.6g) and pyridine (40 ml), and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was treated with aqueous sodium hydroxidesolution and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from ethyl acetate togive the title compound (5.1 g), melting point: 195–197° C.

EXAMPLE 56N-(3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-N,5-dimethylpyrazole-4-carboxamide

N-[3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(1.5 g) and sodium hydride (60% content, 0.2 g) were reacted indimethylformamide (10 ml) under ice-cooling for 1 h. Dimethylformamidesolution (1 ml) containing methyl iodide (0.6 g) was added and themixture was stirred under ice-cooling for 1 h and, after allowed to warmto room temperature, stirred for another 1 h. The reaction mixture wasadded into water and extracted with ethyl acetate. The organic layer waswashed with dilute hydrochloric acid and saturated brine, and dried overanhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. Tetrabutylammonium fluoride (1.4 g),tetrahydrofuran (10 ml) and acetonitrile (10 ml) were added to theresidue, and the mixture was stirred at 80° C. for 2 h. The reactionmixture was added into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. A mixed solvent of ethyl acetate-n-hexane was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-ethanol to give the title compound (0.8g), melting point: 211–212° C.

EXAMPLE 57N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-N-[1-(4-fluorophenyl)-5-methylpyrazol-4-ylcarbonyl]glycine½ isopropanol

N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (3.3 g) andsodium hydride (60% content, 0.3 g) were reacted in dimethylformamide(30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml)containing ethyl bromoacetate (1.4 g) was added and the mixture wasstirred under ice-cooling for 1 h and, after allowed to warm to roantemperature, stirred for another 1 h. The reaction mixture was addedinto water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure.Tetrabutylammonium fluoride (3.0 g), tetrahydrofuran (20 ml) andacetonitrile (20 ml) were added to the residue and the mixture wasstirred at 80° C. for 1 h. The solvent was evaporated under reducedpressure. To the residue was added dilute hydrochloric acid and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof toluene-ethyl acetate was added to the residue to allowcrystallization. The crystals were recrystallized from hydrousisopropanol to give the title compound (0.3 g), melting point: 155–158°C.

EXAMPLE 58 EthylN-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)pyrazol-4-ylcarbonyl]glycine

Dichloroethane solution (15 ml) containing1-(4-fluorophenyl)pyrazole-4-carboxylic acid (1.2 g) and thionylchloride (0.7 g) was stirred at 83° C. for 1 h to give acid chloride. Tothis was added pyridine solution (15 ml) containing ethylN-(3-cyano-4-neopentyloxyphenyl)glycine (1.5 g) under ice-cooling andthe mixture was stirred for 1 h. The reaction mixture was added intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was evaporated under reducedpressure. A mixed solvent of toluene-n-hexane was added to the residueto allow crystallization. The crystals were recrystallized from hydrousethanol to give the title compound (1.7 g), melting point: 153–155° C.

EXAMPLE 59 N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)pyrazol-4-ylcarbonyl]glycine

EthylN-(3-cyano-4-neopentyloxyphenyl)-N-[1(4-fluorophenyl)pyrazol-4-ylcarbonyl]glycine(1.5 g) was added to ethanol (15 ml). 10% aqueous sodium hydroxidesolution (10 ml) was added and the mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducerpressure. To the residue was added dilute hydrochloric acid and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof chloroform-n-hexane was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous aceticacid to give the title compound (0.9 g), melting point: 274–275°C./decomposition

EXAMPLE 60N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-Benzotriazole 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (30 g)and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (21.9 g)were reacted in ethanol (100 ml) at 78° C. for 3 h. After theevaporation of the solvent, aqueous potassium carbonate solution wasadded to the residue and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, after which the solvent was evaporated.Ethyl acetate was added to the residue to allow crystallization. Thecrystals were recrystallized from ethyl acetate to give the titlecompound (25 g), melting point: 179–180° C.

EXAMPLE 614-(1-{2-Cyano-4-[1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide]phenyl}piperidin-4-yloxy)-4-oxobutyricacid

N-[3-Cyano-4-(4-hydroxypiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(1.9 g), succinic anhydride (0.5 g) and a catalytic amount ofp-toluenesulfonic acid 1 hydrate were added to nitrobenzene (40 ml) andthe mixture was stirred at 110° C. for 6 h. The reaction mixture wasice-cooled, diisopropyl ether was added thereto. The precipitatedcrystals was collected by filtration and recrystallized from hydrousethanol to give the title compound (1.2 g), melting point: 219–220° C.

EXAMPLE 62 EthylN-[3-cyano-4-neopentyloxyphenyl]-N-[1-(3-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

Dichloroethane solution (20 ml) containing1-(3-trifluoromethylphenyl)-3-methylpyrazole-4-carboxylic acid (1.6 g)and thionyl chloride (0.8 g) was stirred at 83° C. for 1 h to give acidchloride. Pyridine solution (15 ml) containing ethylN-(3-cyano-4-neopentyloxyphenyl)glycine (1.4 g) was added thereto underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas added into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and the solvent was evaporated underreduced pressure. The residue was recrystallized from ethanol to givethe title compound (1.7 g), melting point: 156–158° C.

EXAMPLE 63N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(3-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

EthylN-(3-cyano-4-neopentyloxyphenyl)-N-[1-(3-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine(1.5 g) was added to ethanol (15 ml). 10% Aqueous sodium hydroxidesolution (10 ml) was added and the mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure. Dilute hydrochloric acid was added to the residue and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof chloroform-n-hexane was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous aceticacid to give the title compound (0.9 g), melting point: 110–112° C.

EXAMPLE 64N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(2,4-difluorophenyl)-5-methylpyrazole-4-carboxamide¼ isopropanol

Dichloroethane solution (20 ml) containing1-(2,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.3 g) andthionyl chloride (1.4 g) was stirred at 83° C. for 30 min to give acidchloride. To this was added pyridine solution (20 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.8 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-isopropanol to givethe title compound (3.1 g), melting point: 149–151° C.

EXAMPLE 65 EthylN-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-methoxyphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

Dichloroethane solution (20 ml) containing1-(4-methoxyphenyl)-3-methylpyrazole-4-carboxylic acid (1.4 g) andthionyl chloride (0.8 g) was stirred at 83° C. for 1 h to give acidchloride. To this was added pyridine solution (15 ml) containing ethylN-(3-cyano-4-neopentyloxyphenyl)glycine (1.4 g) under ice-cooling andthe mixture was stirred for 1 h. The reaction mixture was added intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was evaporated under reducedpressure. The residue was recrystallized form ethanol to give the titlecompound (1.8 g), melting point: 113–114° C.

EXAMPLE 66N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-methoxyphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

EthylN-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-methoxyphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine(1.8 g) was added to ethanol (20 ml). 10% aqueous sodium hydroxidesolution (20 ml) was added and the mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure. Dilute hydrochloric acid was added to the residue and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof chloroform-n-hexane was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous aceticacid to give the title compound (1.6 g), melting point: 98–101° C.

EXAMPLE 67 EthylN-[1-(2-chloro-5-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]-N-[3-cyano-4-neopentyloxyphenyl]glycine

Dichloroethane solution (15 ml) containing1-(2-chloro-5-trifluoromethylphenyl)-3-methylpyrazole-4-carboxylic acid(1.8 g) and thionyl chloride (0.8 g) was stirred at 83° C. for 1 h togive acid chloride. To this was added pyridine solution (15 ml)containing ethyl N-(3-cyano-4-neopentyloxyphenyl)glycine (1.4 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas added into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and the solvent was evaporated underreduced pressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from ethanol to givethe title compound (1.8 g), melting point: 134–135° C.

EXAMPLE 68N-[1-(2-chloro-5-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]-N-(3-cyano-4-neopentyloxyphenyl)glycine

EthylN-[1-(2-Chloro-5-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]-N-(3-cyano-4-neopentyloxyphenyl)glycine(1.8 g) was added to ethanol (15 ml). 10% aqueous sodium hydroxidesolution (15 ml) was added and the mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure, and dilute hydrochloric acid was added. The mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. A mixed solvent ofchloroform-n-hexane was added to the residue to allow crystallization.The crystals were recrystallized from a mixed solvent of diisopropylether-n-hexane to give the title compound (1.2 g), melting point:189–190° C.

EXAMPLE 692-{N-(3-Cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]amino}ethylacetate

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.8 g) andthionyl chloride (1.2 g) was stirred at 83° C. for 1 h to give acidchloride. To this was added pyridine solution (20 ml) containing2-[N-(3-cyano-4-neopentyloxyphenyl)amino]ethylacetate (2.4 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas added into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and the solvent was evaporated underreduced pressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (1.7 g), melting point: 112–113° C.

EXAMPLE 704-[N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]amino]butyricacid

Dichloroethane solution (20 ml) containing1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylic acid (2.0 g) andthionyl chloride (1.3 g) was stirred at 83° C. for 1 h to give acidchloride. To this was added pyridine solution (20 ml) containing ethyl4-[N-(3-cyano-4-neopentyloxyphenyl)amino]butyrate (2.6 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas added into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and the solvent was evaporated underreduced pressure. To the residue were added 10% aqueous sodium hydroxidesolution (30 ml) and ethanol (30 ml) and the mixture was stirred at 78°C. for 1 h. The reaction mixture was cooled to room temperature, afterwhich the mixture was treated with dilute hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. Toluene was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of ethyl acetate-toluene to give the title compound(2.2 g), melting point: 178–180° C.

EXAMPLE 71N-[3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide

Dichloroethane solution (30 ml) containing1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylic acid (3.0 g) andthionyl chloride (1.9 g) was stirred at 83° C. for 30 min to give acidchloride. To this were added5-amino-2-(4-tert-butyldimethylsilyloxypiperidin-1-yl)benzonitrile (4.5g) and pyridine (30 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was treated with aqueous sodium hydroxidesolution and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-n-hexane to give the title compound (5.5 g), meltingpoint: 190–191° C.

EXAMPLE 72N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-N-[1-(4-fluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine½ hydrate

N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide(2.1 g) and sodium hydride (60% content, 0.2 g) were reacted indimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamidesolution (10 ml) containing ethyl bromoacetate (1.0 g) was added and themixture was stirred under ice-cooling for 1 h and, after allowed to warmto room temperature, stirred for another 1 h. The reaction mixture wasadded into water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,after which the solvent was evaporated under reduced pressure. To theresidue were added tetrabutylammonium fluoride (2.0 g), tetrahydrofuran(20 ml) and acetonitrile (20 ml) and the mixture was stirred at 80° C.for 1 h. The solvent was evaporated under reduced pressure. To theresidue was added dilute hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. A mixed solvent oftoluene-ethyl acetate was added to the residue to allow crystallization.The crystals were recrystallized from hydrous isopropanol to give thetitle compound (0.2 g), melting point: 124–125° C.

EXAMPLE 73N-{3-Cyano-4-[bis(2-hydroxyethyl)amino]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g),5-amino-2-[bis(2-hydroxyethyl)amino]benzonitrile (2.0 g),1-hydroxybenzotriazole (1.5 g) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.0 g) were added todimethylformamide (25 ml) and the mixture was stirred at roomtemperature for 5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=100:1) to give an oily substance.Diisopropyl ether was added to the oily substance to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-diisopropyl ether to give the title compound (0.9 g),melting point: 158–159° C.

EXAMPLE 74 EthylN-[3-Cyano-4-neopentyloxyphenyl]-N-[1-(2,4-difluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

Dichloroethane solution (15 ml) containing1-(2,4-difluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.0 g) andthionyl chloride (0.6 g) was stirred at 83° C. for 1 h to give acidchloride. To this was added pyridine solution (15 ml) containing ethylN-(3-cyano-4-neopentyloxyphenyl)glycine (1.4 g) under ice-cooling andthe mixture was stirred for 1 h. The reaction mixture was added intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from ethanol to givethe title compound (0.9 g), melting point: 110° C.

EXAMPLE 75N-[3-Cyano-4-neopentyloxyphenyl]-N-[(1-(2,4-difluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine

EthylN-[3-cyano-4-neopentyloxyphenyl]-N-[1-(2,4-difluorophenyl)-3-methylpyrazol-4-ylcarbonyl]glycine(0.9 g) was added to ethanol (15 ml). 10% aqueous sodium hydroxidesolution (15 ml) was added and the mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure. To the residue was added dilute hydrochloric acid and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof chloroform-n-hexane was added to the residue to allowcrystallization. The crystals were recrystallized from toluene to givethe title compound (0.6 g), melting point: 157–158° C.

EXAMPLE 76N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(2,4-difluorophenyl)-5-methylpyrazole-4-carboxamide

1-(2,4-Difluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.4 g),5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.4 g),1-hydroxybenzotriazole (1.6 g) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.3 g) were added todimethylformamide (25 ml) and the mixture was stirred at roomtemperature for 5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=100:1). Diisopropyl ether was added tothe obtained oily substance to allow crystallization. The crystals wererecrystallized from isopropyl alcohol to give the title compound (2.4g), melting point: 193–194° C.

EXAMPLE 77 Ethyl1-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperidine-4-carboxylate

Dichloroethane solution (30 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (3.3 g) andthionyl chloride (2.1 g) was stirred at 83° C. for 1 h to give acidchloride. To this was added pyridine solution (30 ml) containing ethyl1-(4-amino-2-cyanophenyl)piperidin-4-ylcarboxylate (4.1 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. A mixed solvent oftoluene-diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from a mixed solventof ethyl acetate-diisopropyl ether to give the title compound (4.8 g),melting point: 186–188° C.

EXAMPLE 781-{2-Cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperidine-4-carboxylicacid

Ethyl1-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperidine-4-carboxylate(2.5 g) was added to ethanol (20 ml). 10% aqueous sodium hydroxidesolution (20 ml) was added and the mixture was stirred at a refluxingtemperature for 30 min. The solvent was evaporated under reducedpressure. To the residue was added dilute hydrochloric acid and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. A mixed solventof chloroform-n-hexane was added to the residue to allowcrystallization. The crystals were recrystallized from hydrousdimethylformamide to give the title compound (1.4 g), melting point:260–261° C./decomposition.

EXAMPLE 79N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-3-carboxamide

Dichloroethane solution (30 ml) containing1-(4-fluorophenyl)pyrrole-3-carboxylic acid (1 g) and thionyl chloride(0.7 g) was stirred at 83° C. for 1 h to give acid chloride. The solventwas evaporated under reduced pressure. To the residue was added pyridinesolution (10 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.4 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-diisopropyl etherto give the title compound (0.6 g), melting point: 138–140° C.

EXAMPLE 80N-[3-Cyano-4-(4-piperidinopiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

1-Benzotriazole 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (1.6g) and 5-amino-2-(4-piperidinopiperidin-1-yl)benzonitrile (1.4 g) werereacted in ethanol (15 ml) at 78° C. for 3 h. The solvent wasevaporated. To the residue was added aqueous potassium carbonatesolution and the mixture was extracted with ethyl acetate. The organiclayer was washed with dilute hydrochloric acid and saturated brine, anddried over anhydrous magnesium sulfate, after which the solvent wasevaporated. Diisopropanol was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (0.3 g), melting point: 237–238° C.

EXAMPLE 81N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide1 hydrate

Dichloroethane solution (30 ml) containing1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylic acid (3 g) and thionylchloride (1.9 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (40 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (5 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give the title compound (2.6 g),melting point: 120–121° C.

EXAMPLE 82N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxamide

Dichloroethane solution (25 ml) containing1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylic acid (2.3 g) andthionyl chloride (1.4 g) was stirred at 83° C. for 1 h to give acidchloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (40 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.9 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous dimethylformamide to give the title compound(2.4 g), melting point: 203–204° C.

EXAMPLE 83N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrazole-4-carboxamide

Dichloroethane solution (25 ml) containing1-(4-fluorophenyl)pyrazole-4-carboxylic acid (2.2 g) and thionylchloride (1.6 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (25 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (3.2 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give the title compound (2.1 g),melting point: 205–206° C.

EXAMPLE 84N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-2-carboxamide

1-(4-Fluorophenyl)pyrrole-2-carboxylic acid (2 g),5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.4 g),1-hydroxybenzotriazole (1.8 g) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.2 g) were added todimethylformamide (25 ml) and the mixture was stirred at roomtemperature for 5 h. The reaction mixture was treated with aqueouspotassium carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase:chloroform:methanol=100:1) to give an oily substance. Theobtained oily substance was recrystallized from a mixed solvent oftoluene-n-hexane to give the title compound (1.5 g), melting point:170–171° C.

EXAMPLE 85 tert-Butyl4-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperazin-1-ylcarboxylate

Dichloroethane solution (40 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (3.9 g) andthionyl chloride (2.5 g) was stirred at 83° C. for 1 h to give acidchloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (40 ml) containing5-amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzonitrile (5.4 g)under ice-cooling and the mixture was stirred for 1 h. The reactionmixture was treated with aqueous sodium hydroxide solution and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and the solvent was evaporated under reduced pressure. Diisopropyl etherwas added to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-n-hexane to givethe title compound (5.5 g), melting point: 223–224° C.

EXAMPLE 86 N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

tert-Butyl4-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperazin-1-ylcarboxylate(5.0 g) was added to trifluoroacetic acid (30 ml) under ice-cooling andthe mixture was stirred for 1 h. The reaction mixture was treated withaqueous sodium hydroxide solution and extracted with chloroform. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate, after which the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (3.6 g), melting point: 218–219° C.

EXAMPLE 87N-{3-Cyano-4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamidehydrochloride

N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (2 g),potassium carbonate (0.8 g) and 3-bromopropanol (0.8 g) were added intodimethylformamide (20 ml) and the mixture was stirred at 60° C. for 3 h.The reaction mixture was added into water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, after which the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (mobile phase: chloroform:methanol=50:1). To theresulting oily substance was added hydrogen chloride-isopropyl alcoholsolution to give a hydrochloride, which was recrystallized from hydrousethanol to give the title compound (0.5 g), melting point: 280° C. orhigher.

EXAMPLE 88 Ethyl4-(4-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperazin-1-yl)butyrate

N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(4 g), potassium carbonate (1.6 g) and ethyl 4-bromobutyrate (2.3 g)were added into dimethylformamide (20 ml) and the mixture was stirred at60° C. for 3 h. The reaction mixture was added into water and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate, after which the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized froma mixed solvent of ethyl acetate-n-hexane to give the title compound(3.8 g), melting point: 149–150° C.

EXAMPLE 89N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methyl-1-phenylpyrazole-4-carboxamide

Dichloroethane solution (15 ml) containing5-methyl-1-phenylpyrazole-4-carboxylic acid (1.3 g) and thionyl chloride(0.9 g) was stirred at 83° C. for 1 h to give acid chloride. The solventwas evaporated under reduced pressure. To the residue was added pyridinesolution (15 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.9 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give the title compound (0.9 g),melting point: 214–215° C.

EXAMPLE 901-(2-Chloro-5-trifluoromethylphenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

Dichloroethane solution (15 ml) containing1-(2-chloro-5-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid(2 g) and thionyl chloride (0.9 g) was stirred at 83° C. for 1 h to giveacid chloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (15 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.9 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-diisopropyl etherto give the title compound (1.5 g), melting point: 208–209° C.

EXAMPLE 91 Ethylcis-4-{2-cyano-4-[1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide]phenyl}-2,6-dimethylpiperazin-1-ylacetate

Dichloroethane solution (15 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.2 g) andthionyl chloride (1.4 g) was stirred at 83° C. for 1 h to give acidchloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (20 ml) containing ethylcis-4-(4-amino-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (3.2 g)under ice-cooling and the mixture was stirred for 1 h. The reactionmixture was treated with aqueous sodium hydroxide solution and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (mobilephase:chloroform:methanol=50:1). A solution of hydrogenchloride-isopropyl alcohol was added to the obtained oily substance toallow crystallization. The crystals were recrystallized from hydrousmethanol to give the title compound (4.5 g), melting point: 231–233° C.

EXAMPLE 92cis-4-{2-Cyano-4-[1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide]phenyl}-2,6-dimethylpiperazin-1-ylaceticacid 1 hydrate

Ethylcis-4-{2-cyano-4-[1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide]phenyl}-2,6-dimethylpiperazin-1-ylacetate(3.5 g) and 10% aqueous sodium hydroxide solution (40 ml) were added toethanol (40 ml) and the mixture was stirred at 78° C. for 1 h. Thesolvent was evaporated under reduced pressure. Dilute hydrochloric acidwas added and the precipitated crystals were recrystallized from hydrousethanol to give the title compound (1.2 g), melting point 239–240° C.

EXAMPLE 931-(4-Chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and thionylchloride (1.2 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (20 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.5 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous dimethylformamide to give the title compound(2.8 g), melting point: 220–221° C.

EXAMPLE 94N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-methylphenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and thionylchloride (1.4 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (20 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.9 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate to give the title compound (1.2 g),melting point: 183–184° C.

EXAMPLE 95N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and thionylchloride (1.2 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (20 ml) containing 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.5 g) under ice-cooling and the mixturewas stirred for 1 h. The reaction mixture was treated with aqueoussodium hydroxide solution and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and the solvent was evaporatedunder reduced pressure. Ethyl acetate was added to the residue to allowcrystallization. The crystals were recrystallized from hydrousdimethylformamide to give the title compound (2.8 g), melting point:210–211° C.

EXAMPLE 964-(4-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperazin-1-yl)butyric acid 1 hydrochloride ½ hydrate

Ethyl4-(4-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperazin-1-yl)butyrate(2.0 g) and sodium hydroxide (0.2 g) were added to a mixed solvent ofethanol (20 ml) and water (20 ml), and the mixture was stirred at arefluxing temperature for 1 h. The solvent was evaporated under reducedpressure. Dilute hydrochloric acid was added to the residue and theresulting crystals were recrystallized from hydrous dimethylformamide togive the title compound (1.30 g), melting point: 233° C.

EXAMPLE 971-(4-Bromophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide1 hydrate

Dichloroethane solution (20 ml) containing1-(4-bromophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and thionylchloride (0.76 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (20 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.57 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous dimethylformamide to give the title compound(2.07 g), melting point: 232° C.

EXAMPLE 98N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide1 hydrate

Dichloroethane solution (20 ml) containing1-(4-iodophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and thionylchloride (0.8 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (20 ml) containing5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.8 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas treated with aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with saturated brine, andthe solvent was evaporated under reduced pressure. Ethyl acetate wasadded to the residue to allow crystallization. The crystals wererecrystallized from hydrous dimethylformamide to give the title compound(2.5 g), melting point: 240° C.

EXAMPLE 99N-{3-Cyano-4-[4-(5-methylisoxazol-4-ylcarbonyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

5-Methylisoxazole-4-carbonyl chloride (1.4 g) synthesized according tothe method described in J. Chem. Soc. Perkin Trans. I, pp. 1875–1879(1988) was added to a pyridine solution (20 ml) containingN-[3-cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(4 g) under ice-cooling, and the mixture was stirred for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with dilute hydrochloric acid and saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was evaporated under pressure. Diisopropyl ether was added tothe obtained residue to allow crystallization. The crystals wererecrystallized from hydrous dimethylformamide to give the title compound(2.9 g), melting point: 208° C.

EXAMPLE 100N-{3-Cyano-4-[4-(2-cyano-3-hydroxycrotonoyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

A mixed solvent of ethanol (10 ml) and water (10 ml) containingN-{3-cyano-4-[4-(5-methylisoxazol-4-ylcarbonyl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(0.95 g) and sodium hydroxide (0.1 g) was stirred at a refluxingtemperature for 2 h. The solvent was evaporated under reduced pressure.Dilute hydrochloric acid was added to the residue to allowcrystallization. The crystals were recrystallized from hydrousdimethylformamide to give the title compound (0.45 g), melting point:210° C.

EXAMPLE 101 N-[3-cyano-4-(1-homopiperazinyl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (40 ml) containing1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (3.0 g) andthionyl chloride (2.0 g) was stirred at 83° C. for 1 h to give acidchloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (30 ml) containing5-amino-2-[4-(tert-butoxycarbonyl)homopiperazin-1-yl]benzonitrile (4.8g) under ice-cooling and the mixture was stirred for 1 h. The reactionmixture was treated with aqueous sodium hydroxide solution and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and the solvent was evaporated under reduced pressure. To the residuewas added trifluoroacetic acid (25 ml) under ice-cooling, and themixture was stirred for 1 h. The reaction mixture was treated withaqueous sodium hydroxide solution and extracted with chloroform. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate, after which the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (1.6 g), melting point: 158° C.

EXAMPLE 102N-{3-Cyano-4-[4-(2-hydroxyethyl)homopiperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide½ hydrate

N-[3-Cyano-4-(homopiperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(1.5 g), potassium carbonate (0.6 g) and 2-bromoethyl acetate (0.7 g)were added to dimethylformamide (20 ml) and the mixture was stirred at60° C. for 1 h. The reaction mixture was added into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and the solvent was evaporated under reduced pressure. To the residuewere added 2N aqueous sodium hydroxide solution (10 ml) and ethanol (20ml) and the mixture was stirred at a refluxing temperature for 1 h. Thesolvent was evaporated under reduced pressure and dilute hydrochloricacid was added. The obtained crystals were recrystallized from hydrousethanol to give the title compound (1.1 g), melting point: 124° C.

EXAMPLE 103N-{4-[4-(2-Dimethylaminoethyl)piperazin-1-yl]-3-cyanophenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide¾ hydrate

N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide(2 g), 2-dimethylaminoethyl chloride hydrochloride (0.85 g) andpotassium carbonate (0.8 g) were added to dimethylformamide (20 ml) andthe mixture was stirred at 60° C. for 3 h. The reaction mixture wasadded into water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, and the solvent was evaporated underreduced pressure. Ethanol was added to the residue to allowcrystallization. The crystals were recrystallized from hydrous ethanolto give the title compound (0.3 g), melting point: 185° C.

EXAMPLE 1041-(4-Chlorophenyl)-N-(3-cyano-4-piperidinophenyl)-5-methylpyrazole-4-carboxamide

Dichloroethane solution (20 ml) containing1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) andthionyl chloride (0.9 g) was stirred at 83° C. for 1 h to give acidchloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (20 ml) containing5-amino-2-piperidinobenzonitrile (1.4 g), and the mixture was stirred atroom temperature for 1 h. The reaction mixture was added into water, andthe obtained crystals were recrystallized from hydrous dimethylformamideto give the title compound (2.0 g), melting point: 192° C.

EXAMPLE 105 tert-Butyl4-{4-[1-(4-chlorophenyl)-5-methyl-4-pyrazolecarboxamide]-2-cyanophenyl}piperazin-1-ylcarboxyate

Dichloroethane solution (40 ml) containing1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (3.9 g) andthionyl chloride (2.4 g) was stirred at 83° C. for 1 h to give acidchloride. The solvent was evaporated under reduced pressure. To theresidue was added pyridine solution (40 ml) containing5-amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzonitrile (5.1 g)under ice-cooling and the mixture was stirred for 1 h. The reactionmixture was treated with aqueous sodium hydroxide solution and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and the solvent was evaporated under reduced pressure. Diisopropyl etherwas added to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-n-hexane to givethe title compound (5.5 g), melting point: 251–252° C.

EXAMPLE 106 1-(4-Chlorophenyl)-N-[3-cyano-4-(piperazin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

tert-Butyl4-{4-[1-(4-chlorophenyl)-5-methyl-4-pyrazolecarboxamide]-2-cyanophenylpiperazin-1-ylcarboxylate (9.92 g) was added to trifluoroacetic acid (50ml) under ice-cooling and the mixture was stirred for 1 h. The reactionmixture was treated with aqueous sodium hydroxide solution and extractedwith chloroform. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate, after which the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue to allow crystallization. The crystals were recrystallized fromhydrous ethanol to give the title compound (4.7 g), melting point: 184°C.

EXAMPLE 1071-(4-Chlorophenyl)-N-{3-cyano-4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide1 hydrate

1-(4-Chlorophenyl)-N-[3-cyano-4-(piperazin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide(4.0 g), 3-bromopropanol (1.6 g) and potassium carbonate (1.6 g) wereadded to dimethylformamide (25 ml) and the mixture was stirred at 60° C.for 3 h. The reaction mixture was added into water, and the obtainedcrystals were recrystallized from hydrous dimethylformamide to give thetitle compound (2.5 g), melting point: 213° C.

EXAMPLE 1081-{4-[1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxamide]-2-cyanophenyl}-4-piperidinylbenzoate

Dichloroethane solution (40 ml) containing1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (4 g) and thionylchloride (2.4 g) was stirred at 83° C. for 1 h to give acid chloride.The solvent was evaporated under reduced pressure. To the residue wasadded pyridine solution (40 ml) containing1-(4-amino-2-cyanophenyl)-4-piperidinylbenzoate (5.4 g) underice-cooling and the mixture was stirred for 1 h. The reaction mixturewas added into water, and the obtained crystals were recrystallized fromhydrous dimethylformamide to give the title compound (8.8 g), meltingpoint: 227° C.

EXAMPLE 1091-(4-Chlorophenyl)-N-[3-cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide¾ hydrate

1-{4-[1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxamide]-2-cyanophenyl}piperidin-4-ylbenzoate(8.2 g), 10% aqueous sodium hydroxide solution (90 ml) were addedethanol (90 ml) and the mixture was stirred at 78° C. for 1 h. Theprecipitated crystals were collected by filtration and recrystallizedfrom hydrous dimethylformamide to give the title compound (4.7 g),melting point: 247° C.

EXAMPLE 1104-(1-{4-[1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxamide]-2-cyanophenyl}piperidin-4-yloxy)-4-oxobutyricacid

1-(4-chlorophenyl)-N-[3-cyano-4-(4-hydroxypiperidino)phenyl]-5-methylpyrazole-4-carboxamide(2.0 g), succinic anhydride (0.5 g) and a catalytic amount ofp-toluenesulfonic acid 1 hydrate were added to nitrobenzene (40 ml) andthe mixture was stirred at 110° C. for 6 h. The reaction mixture wasice-cooled, and diisopropyl ether was added thereto. The precipitatedcrystals were filtered and recrystallized from hydrous ethanol to givethe title compound (1.2 g), melting point: 246–248° C.

EXAMPLE 111N-[1-(4-Chlorophenyl)-3-methylpyrazol-4-ylcarbonyl]-N-(3-cyano-4-neopentyloxyphenyl)glycine

Dichloroethane solution (45 ml) containing1-(4-chlorophenyl)-3-methylpyrazole-4-carboxylic acid (2.0 g) andthionyl chloride (1.2 g) was stirred at 83° C. for 30 min to give acidchloride. The acid chloride was added into pyridine solution (80 ml)containing ethyl N-(3-cyano-4-neopentyloxyphenyl)glycine (2.5 g) underice-cooling, and the mixture was stirred for 1 h. The reaction mixturewas added into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and the solvent was evaporated underreduced pressure. Sodium hydroxide (1.8 g), water (40 ml) and ethanol(40 ml) were added to the residue and the mixture was stirred at arefluxing temperature for further 1 h. The solvent was evaporated underreduced pressure, dilute hydrochloric acid was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. n-Hexane was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of toluene-n-hexane to give the title compound (1.7g), melting point: 186–189° C.

EXAMPLE 112N-[1-(4-Bromophenyl)-3-methylpyrazol-4-ylcarbonyl]-N-(3-cyano-4-neopentyloxyphenyl)glycine¼ isopropyl ether

Dichloroethane solution (12 ml) containing1-(4-bromophenyl)-3-methylpyrazole-4-carboxylic acid (1.2 g) and thionylchloride (0.6 g) was stirred at 83° C. for 30 min to give acid chloride.The acid chloride was added pyridine solution (20 ml) containing ethylN-(3-cyano-4-neopentyloxyphenyl)glycine (1.2 g) under ice-cooling andthe mixture was stirred for 1 h. The reaction mixture was added intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was evaporated under reducedpressure. Sodium hydroxide (0.3 g), water (10 ml) and ethanol (10 ml)were added to the residue and the mixture was stirred at a refluxingtemperature for further 1 h. The solvent was evaporated under reducedpressure, dilute hydrochloric acid was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, after whichthe solvent was evaporated under reduced pressure. n-Hexane was added tothe residue to allow crystallization. The crystals were recrystallizedfrom a mixed solvent of toluene-isopropyl ether to give the titlecompound (0.7 g), melting point: 169–170° C.

EXAMPLE 1131-(4-Chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}pyrrole-3-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)pyrrole-3-carboxylic acid (2 g) and5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.67 g), thetitle compound (1.1 g) was obtained, melting point: 196° C.

EXAMPLE 1141-(3-chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and5-amino-2-[4-(2-hydroxyethyl) piperazin-1-yl]benzonitrile (2.5 g), thetitle compound (0.5 g) was obtained, melting point: 176–177° C.

EXAMPLE 115 1-(3,4-Dichlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.67 g), thetitle compound (1.2 g) was obtained, melting point: 195–197° C.

EXAMPLE 1161-(4-Chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamidehydrochloride

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.2 g),1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide(1.3 g) was obtained, melting point: 249–250° C.

¹H-NMR (270 MHz, DMSO-d6) δ(ppm):1.57 (2H, dd, J=2.6, 11.9 Hz), 1.90(2H, d, J=11.2 Hz), 2.25–2.28 (1H, m), 2.47–2.51(4H, m), 2.55 (3H, s),2.75 (2H, t, 11.2 Hz), 3.45 (2H, d, 11.9 Hz), 3.58 (4H, dd, J=4.0, 4.6Hz), 7.16 (1H, d, J=8.6 Hz), 7.5–7.7(4H, m), 7.84 (1H, dd, J=2.6, 8.6Hz), 8.06(1H, d, J=2.6 Hz), 8.30 (1H, s), 9.97 (1H, br).

The above compound was treated with 1N hydrogen chloride-ethanolsolution to give1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamidehydrochloride was obtained, melting point: 286° C. (decomposition).

EXAMPLE 117N-(1-(4-(1-(4-Chlorophenyl)-5-methyl-4-pyrazolecarboxamide)-2-cyanophenyl)piperidine-4-yl)morpholineN-oxide

1-(4-Chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide(1 g) and m-chloroperbenzoic acid (0.4 g) were stirred indichloromethane (10 ml) at room temperature for 8 h. To the reactionmixture was added sodium hydrogen carbonate solution. The organic layerwas extracted with chloroform and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography (chloroform:methanol=1:1) to give thetitle compound (0.3 g), melting point: 200–201° C.

EXAMPLE 1181-(2-Chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamidehydrochloride

Dichloroethane solution (20 ml) containing1-(2-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and thionylchloride (1.4 g) was stirred at 83° C. for 30 min to give acid chloride.A pyridine solution (20 ml) containing 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.5 g) was added thereto under ice-coolingand the mixture was stirred for 1 h. The reaction mixture was treatedwith aqueous sodium hydroxide solution and extracted with ethyl acetate.The organic layer was washed with saturated brine, and the solvent wasevaporated under reduced pressure. 1N Hydrogen chloride-ethanol solutionwas added to the residue to allow crystallization. The crystals wererecrystallized from hydrous ethanol to give the title compound (0.8 g),melting point: 280° C. or higher.

¹H-NMR(270 MHz, CDCl₃) δ(ppm):2.33(3H, s),3.21–3.32(6H, m), 3.55 (2H, d,J=10.9 Hz), 3.66 (2H, d, J=10.9 Hz), 3.84(2H, dd, J=4.4, 5.2 Hz),5.3–5.5(1H, br), 7.28 (1H, d, J=11.2 Hz), 7.57–7.68 (3H, m), 7.74(1H, d, J=9.2Hz), 7.99 (1H, dd, J=2.6, 9.2 Hz), 8.20 (1H, d, J=2.6 Hz), 8.46 (1H, s),10.26 (1H, s), 10.65–10.83 (1H, br)

EXAMPLE 1191-(4-Chlorophenyl)-N-(3-cyano-4-{4-[3-(3-pyridyl)propyl]piperazin-1-yl}phenyl)-5-methylpyrazole-4-carboxamide1 hydrate

3-(3-Pyridyl)propanol (0.2 g) and thionyl chloride (0.2 g) were addedinto dichloroethane (5 ml) and the mixture was stirred at a refluxingtemperature for 1 h. After the evaporation of the solvent,1-(4-chlorophenyl)-N-[3-cyano-4-(piperazin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide (0.6 g), potassium carbonate (0.1g) and dimethylformamide (5 ml) were added and the mixture was stirredat 60° C. for 1 h. The reaction mixture was treated with water, and theorganic layer was extracted with ethyl acetate. The extract was washedwith saturated brine and dried over anhydrous sodium sulfate, afterwhich the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform:methanol=20:1)to give the title compound (0.1 g), melting point: 201–203° C.

EXAMPLE 120 1-(4-Chlorophenyl)-N-(3-cyano-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}phenyl)-5-methylpyrazole-4-carboxamide ¼ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and5-amino-2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}benzonitrile (4.2g), the title compound (2.8 g) was obtained, melting point: 196° C.

EXAMPLE 1211-(4-Chlorophenyl)-N-[3-cyano-4-(1,4-dioxa-8-azaspiro[4,5]deca-8-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (4.2 g) and5-amino-2-(1,4-dioxa-8-azaspiro [4,5]deca-8-yl) benzonitrile (4.6 g),the title compound (5.4 g) was obtained, melting point: 241° C.

EXAMPLE 1221-(4-Chlorophenyl)-N-[3-cyano-4-(4-oxopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

1-(4-Chlorophenyl)-N-[3-cyano-4-(1,4-dioxa-8-azaspiro[4,5]deca-8-yl)phenyl]-5-methylpyrazole-4-carboxamide (5.3 g) and 0.1Nhydrochloric acid (6 ml) were added to tetrahydrofuran (60 ml) and themixture was stirred at a refluxing temperature for 3 h. The organiclayer was extracted with ethyl acetate and dried over anhydrousmagnesium sulfate, after which the solvent was evaporated under reducedpressure. Diisopropyl ether was added to the residue to allowcrystallization. The crystals were recrystallized from ethylacetate-n-hexane to give the title compound (4.5 g), melting point: 238°C.

EXAMPLE 123 Ethyl1-{4-[1-(4-chlorophenyl)-5-methyl-4-pyrazolecarboxamide]-2-cyanophenyl}piperidine-4-carboxylate

By the reaction and treatment in the same manner as in Example 77,except that 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid wasused instead of 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid,the title compound was obtained, melting point: 193° C.

EXAMPLE 1241-{4-[1-(4-Chlorophenyl)-5-methyl-4-pyrazolecarboxamide]-2-cyanophenyl}piperidine-4-carboxylicacid 1 hydrate

By the reaction and treatment in the same manner as in Example 78,except that ethyl1-{4-[1-(4-chlorophenyl)-5-methyl-4-pyrazolecarboxamide]-2-cyanophenyl}piperidine-4-carboxylatewas used instead of ethyl1-{2-cyano-4-[1-(4-fluorophenyl)-5-methyl-4-pyrazolecarboxamide]phenyl}piperidine-4-carboxylate,the title compound was obtained, melting point: 260° C. or higher.

¹H-NMR(270 MHz, CDCl₃) δ(ppm):1.80 (2H, dd, J=3.2, 9.9 Hz),1.95 (2H, dd,J=3.2, 9.9 Hz), 2.40 (1H, ddd, J=3.2, 9.2, 11.2 Hz), 2.55 (3H, s), 2.83(2H, dd, J=9.2, 11.2 Hz),3.2–3.5 (2H, br), 7.18 (1H, d, J=8.6 Hz), 7.61(4H, m), 7.85 (1H, dd, J=2.6, 8.6 Hz), 8.08 (1H, d, J=2.6 Hz), 8.32 (1H,s), 10.01 (1H, s)

EXAMPLE 1252-(4-{4-[1-(4-Chlorophenyl)-5-methyl-4-pyrazolecarboxamide]-2-cyanophenyl]piperazin-1-yl)ethylacetate

1-(4-Chlorophenyl)-N-(3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl-5-methylpyrazolecarboxamide(1 g) was dissolved in pyridine (10 ml). Acetyl chloride (0.17 g) wasadded under ice-cooling and the mixture was stirred for 1 h. Thereaction mixture was treated with aqueous potassium carbonate solution.The organic layer was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate,after which the solvent was evaporated under reduced pressure. n-Hexanewas added to the residue to allow crystallization. The crystals wererecrystallized from a mixed solvent of ethyl acetate-n-hexane to givethe title compound (0.6 g), melting point: 175° C.

EXAMPLE 1261-(4-Chlorophenyl)-N-{3-cyano-4-[4-(N,N-dimethylamino)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (3.3 g) and5-amino-2-[4-(N,N-dimethylamino)piperidin-1-yl]benzonitrile (2.9 g), thetitle compound (1.7 g) was obtained, melting point: 210–213° C.

EXAMPLE 127N-(4-{4-[N,N-Bis(2-hydroxyethyl)amino]piperidin-1-yl}-3-cyanophenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-{4-[N,N-bis(2-hydroxyethyl)amino]piperidin-1-yl}benzonitrile(1.2 g), the title compound (0.2 g) was obtained, melting point:230–233° C.

EXAMPLE 128N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (3 g) and5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (3.7 g), thetitle compound (1.9 g) was obtained, melting point: 164–165° C.

EXAMPLE 1291-(4-Chlorophenyl)-N-{3-cyano-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.7 g) and5-amino-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]benzonitrile (2.0g), the title compound (0.6 g) was obtained, melting point: 240° C.(decomposition).

EXAMPLE 1301-(3-Chloro-4-fluorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3-chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid is (3.5g) and 5-amino-2-[4-(2-hydroxyethyl)-piperazin-1-yl]benzonitrile (3.7g), the title compound (1.0 g) was obtained, melting point: 191° C.

EXAMPLE 1311-(3,4-Dichlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide ½ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.7 g), the titlecompound (1.2 g) was obtained, melting point: 242° C.

EXAMPLE 132N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(3,4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (2.0 g), the titlecompound (0.8 g) was obtained, melting point: 243° C.

EXAMPLE 1331-(3-Chloro-4-fluorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3-chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g)and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (1.9 g), thetitle compound (1.3 g) was obtained, melting point: 266° C.

EXAMPLE 1341-(4-Bromophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-bromophenyl)-5-methylpyrazole-4-carboxylic acid (0.6 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the titlecompound (0.5 g) was obtained, melting point: 250–252° C.

EXAMPLE 135N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-phenyl-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-phenyl-5-methylpyrazole-4-carboxylic acid (0.6 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the titlecompound (0.2 g) was obtained, melting point: 223° C.

EXAMPLE 136 N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl)}-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide1 hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g)and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (0.6 g),the title compound (0.4 g) was obtained, melting point: 218° C.

EXAMPLE 137N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g)and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), thetitle compound (0.1 g) was obtained, melting point: 257° C.(decomposition).

EXAMPLE 138N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.8 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the titlecompound (0.3 g) was obtained, melting point: 226° C.(decomposition).

EXAMPLE 139N-(3-Cyano-4-pyrrolidinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.2 g) and5-amino-2-pyrrolidinobenzonitrile (0.8 g), the title compound (0.8 g)was obtained, melting point: 185° C.

EXAMPLE 1401-(4-Chlorophenyl)-N-(3-cyano-4-pyrrolidinophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.3 g) and5-amino-2-pyrrolidinobenzonitrile (0.8 g), the title compound (0.4 g)was obtained, melting point: 205° C.

EXAMPLE 141N-(3-Cyano-4-homopiperidinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.1 g) and5-amino-2-homopiperidinobenzonitrile (0.8 g), the title compound (0.6 g)was obtained, melting point: 138° C.

EXAMPLE 1421-(4-chlorophenyl)-N-(3-cyano-4-homopiperidinophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.1 g) and5-amino-2-homopiperidinobenzonitrile (0.8 g), the title compound (0.5 g)was obtained, melting point: 131° C.

EXAMPLE 143N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-fluorophenyl)pyrrole-3-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)pyrrole-3-carboxylic acid (0.5 g) and5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (0.7 g), the titlecompound (0.4 g) was obtained, melting point: 182–183° C.

EXAMPLE 1441-(3-Chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.4 g), the titlecompound (1.0 g) was obtained, melting point: 210° C.

EXAMPLE 145N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g)and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.4 g), thetitle compound (1.0 g) was obtained, melting point: 215–216° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.55–1.61 (2H, m), 1.91 (2H, d, J=11.2Hz), 2.28–2.31 (1H, m), 2.48–2.60 (4H, m), 2.60 (3H, s), 2.77 (2H, t,J=11.2 Hz), 3.47 (2H, d, J=11.8 Hz), 3.50–3.59 (4H, m), 7.19 (1H, d,J=9.2 Hz), 7.80–7.95 (5H, m), 8.08 (1H, d, J=2.0 Hz), 8.35 (1H, s),10.02 (1H, s).

EXAMPLE 1461-(2-Chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(2-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.2 g), the titlecompound (0.79 g) was obtained, melting point: 218° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.57 (2H, ddd, J=3.0, 11.2, 11.7 Hz),1.90 (2H, d, J=11.7 Hz), 2.25–2.30 (1H, m), 2.33 (3H, s), 2.47–2.51 (4H,m), 2.77 (2H, t, J=11.7 Hz), 3.47 (2H, d, J=11.7 Hz), 3.58–3.60 (4H, m),7.19 (1H, d, J=9.3 Hz), 7.53–7.66 (3H, m), 7.75 (1H, d, J=9.8 Hz), 7.85(1H, dd, J=2.4, 9.3 Hz), 8.77 (1H, d, J=2.4 Hz), 8.32 (1H, s), 10.00(1H, s).

EXAMPLE 147N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-iodophenyl)-5-methylpyrazole-4-carboxylic acid (1.2 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1 g), the titlecompound (1.0 g) was obtained, melting point: 280° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.57 (2H, dd, J=11.2, 11.7 Hz), 1.91(2H, d, J=10.5 Hz), 2.26–2.34 (1H, m), 2.49–2.54 (4H, m), 2.55 (3H, s),2.77 (2H, dd, J=10.5, 11.7 Hz), 3.47 (2H, d, J=11.7 Hz), 3.57–3.60 (4H,m), 9.19 (1H, d, J=9.3 Hz), 7.37 (2H, dd, J=2.0, 6.8 Hz), 7.86 (1H, dd,J=2.4, 9.3 Hz), 7.91 (2H, dd, J=2.0, 6.8 Hz), 8.06 (1H, d, J=2.0 Hz),8.30 (1H, s), 9.98 (1H, s).

EXAMPLE 148N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-methylphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.4 g), the titlecompound (0.94 g) was obtained, melting point: 243° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.53–1.60 (2H, m), 1.91 (2H, d, J=11.7Hz), 2.27–2.31 (1H, m), 2.40 (3H, s), 2.50–2.52 (4H, m), 2.77 (2H, dd,J=10.2, 11.7 Hz), 3.33–3.37 (4H, m), 3.38 (3H, s), 3.46 (2H, d, J=11.7Hz), 3.56–3.60 (4H, m), 7.19 (1H, d, J=11.2 Hz), 7.36 (2H, d, J=8.6 Hz),7.41 (2H, d, J=8.6 Hz), 7.84 (1H, dd, J=2.7, 11.2 Hz), 8.06 (1H, d,J=2.7 Hz), 8.27 (1H, s), 9.96 (1H, s).

EXAMPLE 149N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (1.2 g), the titlecompound (1.3 g) was obtained, melting point: 238° C.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.52–1.62 (2H, m), 1.90 (2H, d,J=11.8 Hz), 2.25–2.32 (1H, m), 2.48–2.50 (4H, m), 2.49 (3H, s), 2.76(2H, t, J=11.2 Hz), 3.46 (2H, d, J=11.8 Hz), 3.57–3.59 (4H, m), 3.83(3H, s), 7.09 (2H, d, J=8.3 Hz), 7.17 (1H, d, J=8.8 Hz), 7.44 (2H, d,J=8.3 Hz), 7.84 (1H, dd, J=2.5, 8.8 Hz), 8.07 (1H, d, J=2.5 Hz), 8.25(1H, s), 9.94 (1H, s).

EXAMPLE 1501-(4-Chlorophenyl)-N-[3-cyano-4-(4-thiomorpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.67 g) and5-amino-2-(4-thiomorpholinopiperidin-1-yl)benzonitrile (0.8 g) wereadded to pyridine (10 ml) and the reaction was conducted for 1 h at roomtemperature. To the reaction mixture was added aqueous potassiumcarbonate solution and the precipitated crystals were recrystallizedfrom hydrous dimethylformamide to give the title compound (0.52 g),melting point: 256° C./decomposition.

EXAMPLE 1511-(4-Chlorophenyl)-N-(3-cyano-4-[4-(N-(2-hydroxyethyl)amino)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

The reaction and treatment in the same manner as in Example 150 wereconducted using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylicchloride (1.19 g) and5-amino-2-[4-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino)piperidin-1-yl]benzonitrileand the resulting mixture was further stirred in trifluoroacetic acid(10 ml) under ice-cooling for 1 h. The reaction mixture was treated withaqueous sodium hydroxide solution and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was recrystallized from ethanol to give the title compound (0.29g), melting point: 181° C.

EXAMPLE 1521-(4-Chlorophenyl)-N-{3-cyano-4-[4-(N-(2-hydroxyethyl)-N-methylamino)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.73 g) and5-amino-2-[4-[N-(2-hydroxyethyl)-N-methylamino]piperidin-1-yl]benzonitrile(0.65 g), the title compound (0.2 g) was obtained, melting point: 186°C.

EXAMPLE 153N-{3-Cyano-4-[4-(N-(2-hydroxyethyl)amino)piperidin-1-yl]phenyl}-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide

The reaction and treatment in the same manner as in Example 64 wereconducted using1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (1.94 g)and5-amino-2-[4-(N-tert-butoxycarbonyl-2-hydroxyethylamino)piperidin-1-yl]benzonitrile(2.59 g) and the resulting mixture was further stirred intrifluoroacetic acid (10 ml) under ice-cooling for 1 h. The reactionmixture was treated with aqueous sodium hydroxide solution and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was recrystallized from a mixedsolvent of dimethylformamide-water to give the title compound (0.34 g),melting point: 202° C.

EXAMPLE 1541-(4-Chlorophenyl)-N-[3-cyano-4-(4-piperidinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.86 g) and5-amino-2-(4-piperidinopiperidin-1-yl)benzonitrile (0.8 g), the titlecompound (0.78 g) was obtained, melting point: 252° C./decomposition. b3

EXAMPLE 155N-[3-Carbamoyl-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide5/2 hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzamide (2.5 g), the titlecompound (0.94 g) was obtained, melting point: 270° C.

1H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.53–1.59 (2H, m), 1.93 (2H, d, J=12.2Hz), 2.21–2.29(1H, m), 2.45–2.57 (4H, m), 2.56 (3H, s), 2.70 (2H, d,J=11.3 Hz), 3.11 (2H, d, J=11.3 Hz), 3.55–3.62 (4H, m), 7.23 (1H, d,J=8.3 Hz), 7.24 (1H, brs), 7.58–7.64 (4H, m), 7.80–7.82 (1H, m),8.09–8.14 (1H, m), 8.36 (1H, s), 8.96 (1H, s), 9.92(1H, s).

EXAMPLE 1561-(4-Chlorophenyl)-N-[3-cyano-4-(4-piperazinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 151 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.66 g) and5-amino-2-[4-(4-tert-butoxycarbonylpiperazin-1-yl)piperidin-1-yl]benzonitrile(1.0 g), the title compound (0.54 g) was obtained, melting point: 226°C.

EXAMPLE 157N-{4-[4-(4-Acetylpiperazin-1-yl)piperidin-1-yl]-3-cyanophenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 125 using1-(4-chlorophenyl)-N-[3-cyano-4-(4-piperazinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide(0.18 g), the title compound (0.16 g) was obtained, melting point: 247°C.

EXAMPLE 158N-[3-Bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (4.8 g) and3-bromo-4-(4-morpholinopiperidin-1-yl)aniline (5 g), the title compound(4.5 g) was obtained, melting point: 205–210° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.7 (2H, m), 1.8–1.9 (2H, m),2.2–2.3 (1H, m), 2.5–2.55 (4H, m), 2.55 (3H, s), 2.55–2.65 (2H, m),3.2–3.4 (2H, m), 3.55–3.65 (4H, m), 7.15 (1H, d, J=8.8 Hz), 7.5–7.7 (5H,m), 8.06 (1H, d, J=2.5 Hz), 8.31 (1H, s), 9.88 (1H, s, NH)

EXAMPLE 159N-[3-Bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (1.7g) and 3-bromo-4-(4-morpholinopiperidin-1-yl)aniline (2.0 g), the titlecompound (2.1 g) was obtained, melting point: 220–230° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m),2.25–2.35 (1H, m), 2.45–2.55 (4H, m), 2.62 (3H, s), 2.55–2.65 (2H, m),3.2–3.3 (2H, m), 3.55–3.65 (4H, m), 7.15 (1H, d, J=8.8 Hz), 7.67 (1H,dd, J=1.9, 8.8 Hz), 7.83 (2H, d, J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz), 8.06(1H, d, J=1.9 Hz), 8.36 (1H, s), 9.92 (1H, s).

EXAMPLE 1601-(4-Chlorophenyl)-N-[2-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.81 g) and2-amino-5-(4-morpholinopiperidin-1-yl)benzonitrile (0.9 g), the titlecompound (0.29 g) was obtained, melting point: 212–213° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.4–1.5 (2H, m), 1.8–1.9 (2H, m),2.3–2.4 (1H, m), 2.5–2.55 (4H, m), 2.54 (3H, s), 2.7–2.8 (2H, m),3.5–3.6 (4H, m), 3.75–3.85 (2H, m), 7.3–7.35 (3H, m), 7.61 (2H, d, J=8.8Hz), 7.64 (2H, d, J=8.8 Hz), 8.29 (1H, s), 9.98 (1H, s).

EXAMPLE 161N-[2-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide1 hydrate

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.9g) and 2-amino-5-(4-morpholinopiperidin-1-yl)benzonitrile (0.9 g), thetitle compound (0.67 g) was obtained, melting point: 210–212° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.4–1.5 (2H, m), 1.8–1.9 (2H, m),2.3–2.35 (1H, m), 2.4–2.55 (4H, m), 2.61 (3H, s), 2.7–2.8 (2H, m),3.55–3.65 (4H, m), 3.8–3.85 (2H, m), 7.3–7.35 (3H, m), 7.84 (2H, d,J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz), 8.34 (1H, s), 10.02 (1H, s).

EXAMPLE 1621-(4-Chlorophenyl)-5-methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-nitrophenyl]pyrazole-4-carboxamide

1-(4-Chlorophenyl)-N-(4-chloro-3-nitrophenyl)-5-methylpyrazole-4-carboxamide(1.6 g) and 4-morpholinopiperidine (2.4 g) were added to dimethylsulfoxide (20 ml) and the mixture was stirred at a refluxing temperaturefor 1.5 h. After cooling to room temperature, water was added and theprecipitated solid was collected by filtration and extracted withchloroform. The organic layer was washed with 30% potassium carbonateand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (mobile phase:chloroform/methanol)and recrystallized from hydrous dimethylformamide to give the titlecompound (0.7 g), melting point: 195–200° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.45–1.55 (2H, m), 1.8–1.9 (2H, m),2.25–2.35 (1H, m), 2.5–2.55 (4H, m), 2.56 (3H, s), 2.7–2.8 (2H, m),3.15–3.2 (2H, m), 3.55–3.60 (4H, m), 7.35 (1H, d, J=9.3 Hz), 7.60 (2H,d, J=8.8 Hz), 7.64 (2H, d, J=8.8 Hz), 7.88 (1H, dd, J=1.9, 9.3 Hz), 8.30(1H, d, J=1.9 Hz), 8.33 (1H, s), 10.09 (1H, s).

EXAMPLE 1635-Methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-nitrophenyl]-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide

The reaction and treatment in the same manner as in Example 162 usingN-(4-chloro-3-nitrophenyl)-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide(1.0 g) and 4-morpholinopiperidine (1.4 g), the title compound (0.12 g)was obtained, melting point: 225–230° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m),2.25–2.35 (1H, m), 2.5–2.6 (4H, m), 2.63 (3H, s), 2.75–2.85 (2H, m),3.15–3.25 (2H, m), 3.55–3.60 (4H, m), 7.36 (1H, d, J=8.8 Hz), 7.84 (2H,d, J=8.8 Hz), 7.88 (1H, dd, J=2.4, 8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 8.30(1H, d, J=2.4 Hz), 8.38 (1H, s), 10.12 (1H, s).

EXAMPLE 1641-(4-Chlorophenyl)-5-methyl-N-[3-methyl-4-(4-morpholinopiperidin-1-yl)phenyl]pyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.0 g) and3-methyl-4-(4-morpholinopiperidin-1-yl)aniline (1.07 g), the titlecompound (1.0 g) was obtained, melting point: 235–245° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(PPM): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m), 2.24(3H, s), 2.4–2.6 (7H, m), 2.55 (3H, s), 3.0–3.1 (2H, m), 3.5–3.6 (4H,m), 6.98 (1H, d, 3=8.3 Hz), 7.4–7.5 (2H, m), 7.59 (2H, d, J=8.8 Hz),7.63 (2H, d, J=8.8 Hz), 8.31 (1H, s), 9.68 (1H, s).

EXAMPLE 1655-Methyl-N-[3-methyl-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide1 hydrate

By the reaction and treatment the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl) pyrazole-4-carboxylic chloride (1.0g) and 3-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.95 g), thetitle compound (1.1 g) was obtained, melting point: 252–255° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m),2.2–2.3 (1H, m), 2.24 (3H, s), 2.45–2.55 (4H, m), 2.55–2.65 (2H, m),2.62 (3H, s), 3.0–3.1 (2H, m), 3.5–3.6 (4H, m), 6.99 (1H, d, J=8.7 Hz),7.4–7.5 (2H, m), 7.83 (2H, d, J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz), 8.36(1H, s), 9.73 (1H, s).

EXAMPLE 1661-(4-Chlorophenyl)-N-[3-chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and3-chloro-4-(4-morpholinopiperidin-1-yl)aniline (0.7 g), the titlecompound (0.51 g) was obtained, melting point: 238–240° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.85–1.95 (2H, m),2.2–2.3 (1H, m), 2.5–2.55 (4H, m), 2.55 (3H, s), 2.6–2.7 (2H, m),3.2–3.4 (2H, m), 3.55–3.65 (4H, m), 7.14 (1H, d, J=8.7 Hz), 7.55–7.65(5H, m), 7.88 (1H, s), 8.31 (1H, s), 9.89 (1H, s).

EXAMPLE 167N-[3-Chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamidedimethylformamide

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.6g) and 3-chloro-4-(4-morpholinopiperidin-1-yl)aniline (0.61 g), thetitle compound (0.79 g) was obtained, melting point: 252–256° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m),2.2–2.3 (1H, m), 2.5–2.65 (6H, m), 2.62 (3H, s), 3.3–3.4 (2H, m),3.4–3.6 (4H, m), 7.15 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=8.8 Hz),7.8–7.95 (5H, m), 8.36 (1H, s), 9.93 (1H, s).

EXAMPLE 1681-(4-Chlorophenyl)-N-[3-cyano-4-(4-phenylpiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and5-amino-2-(4-phenylpiperidin-1-yl)benzonitrile (0.65 g), the titlecompound (0.7 g) was obtained, melting point: 186–188° C.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.8–1.95 (4H, m), 2.56 (3H, s),2.7–2.75 (1H, m), 2.85–2.95 (2H, m), 3.55–3.6 (2H, m), 7.25 (1H, d,J=9.3 Hz), 7.3–7.4 (5H, m), 7.61 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=8.8Hz), 7.88 (1H, dd, J=2.4, 9.3 Hz), 8.10 (1H, d, J=2.4 Hz), 8.52 (1H, s),10.01 (1H, s).

EXAMPLE 169N-[4-(1-Benzylpiperidin-4-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-(1-benzylpiperidin-4-yloxy)benzonitrile (1.2 g), the titlecompound (0.6 g) was obtained, melting point: 194° C.

EXAMPLE 1701-(4-Chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(1.1 g), the title compound (0.9 g) was obtained, melting point: 276° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): d: 1.44 (2H, ddd, J=4.0, 11.7, 12.2Hz), 1.75 (2H, d, J=12.2 Hz), 2.41–2.49 (1H, m), 2.56 (3H, s), 2.66–2.69(4H, m), 3.07–3.12 (4H, m), 3.27–3.36 (2H, m), 3.90 (2H, d, J=10.7 Hz),7.19 (1H, d, J=8.8 Hz), 7.59–7.65 (4H, m), 7.86 (1H, dd, J=2.5, 8.8 Hz),8.08 (1H, d, J=2.5 Hz), 8.31 (1H, s), 10.00 (1H, s).

EXAMPLE 1711-(4-Chlorophenyl)-N-[3-ethynyl-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide½ hydrate

A suspension ofN-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide(1 g), bistriphenylphosphinepalladium dichloride (0.38 g), cuprousiodide (0.06 g), trimethylsilylacetylene (0.53 g) and piperidine (50 ml)was refluxed under heating for 15 h. The solvent was evaporated and theresidue was purified by silica gel column chromatography (mobile phase:ethyl acetate/hexane). The resulting residue was dissolved in methanol(10 ml) and potassium carbonate (170 mg) was added. The mixture wasstirred at room temperature for 1 h. After the reaction, potassiumcarbonate was filtered off. The filtrate was purified by silica gelcolumn chromatography (mobile phase: chloroform/methanol) andrecrystallized from a mixed solvent of chloroform-diisopropyl ether togive the title compound (27 mg), melting point: 203–205° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m),2.2–2.3 (1H, m), 2.50–2.55 (4H, m), 2.55 (3H, s), 2.5–2.6 (2H, m),3.5–3.6 (6H, m), 4.37 (1H, s), 6.98 (1H, d, J=8.8 Hz), 7.5–7.65 (5H, m),7.81 (1H, d, J=2.5 Hz), 8.30 (1H, s), 9.78 (1H, s).

EXAMPLE 172N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-(4-trifluoromethylphenyl)pyrazole4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic acid (1.1 g)and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(1.1 g), the title compound (1.0 g) was obtained, melting point: 274° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, dq, J=3.6, 11.7 Hz), 1.74(2H, d, J=11.7 Hz), 2.41–2.50 (1H, m), 2.62 (3H, s), 2.50–2.63 (4H, m),3.09–3.15 (4H, m), 3.26–3.34 (2H, m), 3.90 (2H, d, J=11.7 Hz), 7.18 (1H,d, J=8.8 Hz), 7.83 (2H, d, J=8.3 Hz), 7.86 (1H, dd, J=2.4, 8.8 Hz), 7.95(2H, d, J=8.3 Hz), 8.08 (1H, d, J=2.4 Hz), 8.35 (1H, s), 10.03 (1H, s).

EXAMPLE 1731-(4-Chlorophenyl)-N-{4-[4-(4-chlorophenyl)piperazin-1-yl]-3-cyanophenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic-acid (0.5 g) and5-amino-2-[4-(4-chlorophenyl)piperazin-1-yl]benzonitrile (0.6 g), thetitle compound (0.5 g) was obtained, melting point: 265° C.

EXAMPLE 1741-Benzyl-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-3-methylpyrazole-4-carboxamide⅓ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-benzyl-3-methylpyrazole-4-carboxylic acid (0.6 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.8 g), the titlecompound (0.63 g) was obtained, melting point: 193° C.

EXAMPLE 175 N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-3-methyl-1-(2-phenylethyl) pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using3-methyl-1-(2-phenylethyl)pyrazole-4-carboxylic acid (0.64 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.8 g), the titlecompound (0.8 g) was obtained, melting point: 188° C.

EXAMPLE 1761-(4-Chlorophenyl)-N-{3-cyano-4-[4-(2-methoxyethylamino)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 151 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and5-amino-2-[4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]piperidin-1-yl]benzonitrile (0.9 g), the title compound (0.6 g)was obtained, melting point: 194° C.

EXAMPLE 1771-(4-Chlorophenyl)-N-{(3-cyano-4-[4-[N-(2-methoxyethyl)-N-methylamino]piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.53 g) and5-amino-2-[4-[N-(2-methoxyethyl)-N-methylamino]piperidin-1-yl]benzonitrile(0.6 g), the title compound (0.66 g) was obtained, melting point: 187°C.

EXAMPLE 1781-(4-Chlorophenyl)-5-methyl-N-[4-(4-morpholinopiperidin-1-yl)-3-trifluoromethylphenyl]pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.77 g) and4-(4-morpholinopiperidin-1-yl)-3-trifluoromethylaniline (1 g), the titlecompound (1.1 g) was obtained, melting point: 193–194° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.9 (2H, m),2.2–2.3 (1H, m), 2.5–2.6 (4H, m), 2.56 (3H, s), 2.7–2.8 (2H, m), 2.9–3.0(2H, m), 3.5–3.6 (4H, m), 7.51 (1H, d, J=8.8 Hz), 7.55–7.7 (4H, m), 7.98(1H, dd, J=2.5, 8.8 Hz), 8.09 (1H, d, J=2.5 Hz), 8.34 (1H, s), 10.06(1H, s).

EXAMPLE 179N-{4-[4-Bis(2-methoxyethyl)aminopiperidin-1-yl]-3-cyanophenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.83 g) and5-amino-2-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]benzonitrile (0.9g), the title compound (0.52 g) was obtained, melting point: 152° C.

EXAMPLE 180N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(2-pyridyl)pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using5-methyl-1-(2-pyridyl)pyrazole-4-carboxylic acid (2.0 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.88 g), the titlecompound (1.52 g) was obtained, melting point: 251° C.

EXAMPLE 181N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(2-phenylethyl)pyrazole-4-carboxamide

The reaction and treatment in the same manner as in Example 64 wereconducted using 5-methyl-1-(2-phenylethyl)pyrazole-4-carboxylic acid(0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.75 g)and the resulting product was recrystallized from ethyl acetate to givethe title compound (0.4 g), melting point: 195° C.

EXAMPLE 1821-Benzyl-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide⅓ hydrate

The reaction and treatment in the same manner as in Example 64 wereconducted using 1-benzyl-5-methylpyrazole-4-carboxylic acid (0.7 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.93 g) and theresulting product was recrystallized from a mixed solvent of ethylacetate-diisopropyl ether to give the title compound (0.36 g), meltingpoint: 155° C.

EXAMPLE 1831-(4-Chlorophenyl)-N-[3-cyano-4-(4-methoxymethoxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.62 g) and5-amino-2-(4-methoxymethoxypiperidin-1-yl) benzonitrile (0.63 g), thetitle compound (0.33 g) was obtained, melting point: 186–188° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.6–1.7 (2H, m), 1.9–2.0 (2H, m), 2.56(3H, s), 2.9–3.0 (2H, m), 3.29 (3H, s), 3.3–3.4 (2H, m), 3.65–3.75 (1H,m), 4.67 (2H, s), 7.21 (1H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.64(2H, d, J=8.8 Hz), 7.85 (1H, d, J=8.8 Hz), 8.07 (1H, s), 8.31 (1H, s),10.00 (1H, s).

EXAMPLE 184 1-(4-Chlorophenyl)-N-[3-cyano-4-[4-(2-methoxyethoxy)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.13 g) and5-amino-2-[4-(2-methoxyethoxy)piperidin-1-yl]benzonitrile (0.14 g), thetitle compound (0.05 g) was obtained, melting point: 180–182° C.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.6–1.7 (2H, m), 1.9–2.0 (2H, m),2.50 (3H, s), 2.85–2.95 (2H, m), 3.27 (3H, s), 3.2–3.3 (2H, m), 3.4–3.5(3H, m), 3.5–3.6 (2H, m), 7.20 (1H, d, J=8.8 Hz), 7.60 (2H, d, J=9.3Hz), 7.64 (2H, d, J=9.3 Hz), 7.85 (1H, dd, J=8.8, 2.5 Hz), 8.07 (1H, d,J=2.5 Hz), 8.31 (1H, s), 10.00 (1H, s).

EXAMPLE 1851-(4-Chlorophenyl)-N-[3,5-dichloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.77 g) and3,5-dichloro-4-(4-morpholinopiperidin-1-yl)aniline (1.0 g), the titlecompound (1.0 g) was obtained, melting point: 246–248° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.5–1.6 (2H, m), 1.8–1.85 (2H, m),2.25–2.35 (1H, m), 2.5–2.55 (4H, m), 2.55 (3H, s), 2.95–3.00 (2H, m),3.2–3.3 (2H, m), 3.55–3.65 (4H, m), 7.60 (2H, d, J=9.3 Hz), 7.64 (2H, d,J=9.3 Hz), 7.80 (1H, s), 7.88 (1H, s), 8.31 (1H, s), 10.02 (1H, s).

EXAMPLE 186N-[3,5-Dichloro-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide½ hydrate

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.87g) and 3,5-dichloro-4-(4-morpholinopiperidin-1-yl)aniline (1.0 g), thetitle compound (1.2 g) was obtained, melting point: 252–254° C.

¹H-NMR (400 MHz, DMSO-{) δ(ppm): 1.5–1.6 (2H, m), 1.75–1.85 (2H, m),2.25–2.35 (1H, m), 2.5–2.55 (4H, m), 2.61 (3H, s), 2.95–3.0 (2H, m),3.2–3.3 (2H, m), 3.55–3.65 (4H, m), 7.8–8.00 (6H, m), 8.36 (1H, s),10.07 (1H, s).

EXAMPLE 187N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-5-methyl-1-phenylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using5-methyl-1-phenylpyrazole-4-carboxylic acid (0.4 g) and5-mino-2-(4-hydroxypiperidin-1-yl)benzonitrile (0.4 g), the titlecompound (0.3 g) was obtained, melting point: 182° C.

EXAMPLE 188N-{3-Cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1 g) and5-amino-2-[4-(2-hydroxyethyl)piperidin-1-yl]benzonitrile (1.6 g), thetitle compound (0.2 g) was obtained, melting point: 186° C.

EXAMPLE 1891-(4-Chlorophenyl)-N-{3-cyano-4-[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide1 hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and5-amino-2-[4-(4-hydroxypiperidin-1-yl) piperidin-1-yl]benzonitrile (0.6g), the title compound (0.2 g) was obtained, melting point: 213° C.

EXAMPLE 190 1-(4-Chlorophenyl)-N-[3-cyano-(4-morpholinopiperidin-1-yl)phenyl]pyrrole-3-carboxamide ¼ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)pyrrole-3-carboxylic acid (0.6 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.7 g), the titlecompound (0.49 g) was obtained, melting point: 220° C.

EXAMPLE 1911-(4-Chlorophenyl)-N-[3-cyano-(4-morpholinomethylpiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.17 g) and5-amino-2-[4-(4-morpholinomethylpiperidin-1-yl)phenyl]benzonitrile (1.25g), the title compound (0.94 g) was obtained, melting point: 235° C.

EXAMPLE 192N-[3-Cyano-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-nitrophenyl)pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-nitrophenyl)pyrazole-4-carboxylic acid (1.6 g) and5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.8 g), the titlecompound (0.8 g) was obtained, melting point: 265° C./decomposition.

EXAMPLE 193N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.6 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(0.8 g), the title compound (0.6 g) was obtained, melting point: 240° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, dq, J=3.4, 11.7 Hz), 1.75(2H, d, J=12.2 Hz), 2.40–2.50 (1H, m), 2.50 (3H, s), 2.67 (4H, m), 3.10(4H, m), 3.31 (2H, d, J=13.6 Hz), 3.90 (2H, d, J=13.6 Hz), 7.19 (1H, d,J=8.8 Hz), 7.41 (2H, t, J=8.8 Hz), 7.60 (2H, dd, J=4.8, 8.8 Hz), 7.87(1H, dd, J=2.4, 8.8 Hz), 8.09 (1H, d, J=2.4 Hz), 8.29 (1H, s), 10.00(1H, s).

EXAMPLE 194N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-fluorophenyl)pyrrole-3-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-fluorophenyl)pyrrole-3-carboxylic acid (0.3 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(0.5 g), the title compound (0.4 g) was obtained, melting point: 240° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, dq, J=4.0, 12.2 Hz), 1.74(2H, d, J=12.2 Hz), 2.41–2.50 (1H, m), 2.67 (4H, m), 3.10 (4H, m), 3.27(2H, d, J=11.2 Hz), 3.89 (2H, d, J=11.8 Hz), 6.85 (1H, d, J=9.3 Hz),7.19 (1H, d, J=9.3 Hz), 7.37 (2H, t, J=8.8 Hz), 7.43 (1H, s), 7.70 (2H,dd, J=4.4, 8.8 Hz), 7.89 (1H, dd, J=2.4, 9.3 Hz), 8.05(1H, s), 8.10 (1H,d, J=2.4 Hz), 9.82 (1H, s).

EXAMPLE 1951-(4-Chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}pyrrole-3-carboxamide⅖ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)pyrrole-3-carboxylic acid (0.5 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(0.7 g), the title compound (0.4 g) was obtained, melting point: 224° C.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.38–1.73 (2H, m), 1.74(2H, d, J=12.2Hz), 2.41–2.50 (1H, m), 2.67 (4H, m), 3.10 (4H, m), 3.27 (2H, d, J=11.7Hz), 3.89 (2H, d, J=11.7 Hz), 6.86 (1H, m), 7.19 (1H, d, J=9.3 Hz), 7.49(1H, m), 7.67 (2H, d, J=9.2 Hz), 7.70 (2H, d, J=9.2 Hz), 7.88 (1H, dd,J=2.4, 9.3 Hz), 8.09 (1H, d, J=2.4 Hz), 8.11 (1H, s), 9.84 (1H, s).

EXAMPLE 1961-(3,4-Dichlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide1 hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(1.1 g), the title compound (0.6 g) was obtained, melting point: 242° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, dq, J=3.5, 11.8 Hz), 1.73(2H, d, J=11.8 Hz), 2.41–2.50 (1H, m), 2.51 (3H, s), 2.67 (4H, m), 3.10(3H, m), 3.27 (2H, d, J=11.7 Hz), 3.91 (2H, d, J=10.2 Hz), 7.18 (1H, d,J=8.8 Hz), 7.60(1H, dd, J=2.5, 8.8 Hz), 7.85 (1H, dd, J=2.5, 8.8 Hz),7.92 (1H, d, J=2.5 Hz), 8.08 (1H, d, J=2.5 Hz), 8.33 (1H, s), 10.01 (1H,s)

EXAMPLE 1971-(4-Bromophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-bromophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.0 g), the title compound (0.7 g) wasobtained, melting point: 288° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, ddd, J=2.9, 11.5, 12.2 Hz),1.75 (2H, d, J=12.2 Hz), 2.42–2.51 (1H, m), 2.56 (3H, s), 2.67 (4H, m),3.10 (4H, m), 3.28 (2H, d, J=11.5 Hz), 3.90 (2H, d, J=7.8 Hz), 7.19 (1H,d, J=8.3 Hz), 7.53 (2H, 3, J=8.8 Hz), 7.77 (2H, 3, J=8.8 Hz), 7.86 (1H,dd, J=2.4, 8.3 Hz), 8.08 (1H, d, J=2.4 Hz), 8.31 (1H, s), 10.00 (1H, s).

EXAMPLE 198N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 64 using1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(1.0 g), the title compound (0.8 g) was obtained, melting point: 235° C.

H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.42 (2H, ddd, J=4.9, 11.2, 11.7 Hz),1.73 (2H, d, J=12.2 Hz), 2.41–2.50 (1H, m), 2.56 (3H, s), 2.66 (4H, m),3.10 (4H, m), 3.27 (2H, d, J=11.7 Hz), 3.90 (2H, d, J=10.3 Hz), 7.17(1H, d, J=8.8 Hz), 7.19 (1H, m), 7.63 (1H, m), 7.78 (1H, m), 7.86 (1H,d, J=8.8 Hz), 8.09 (1H, s), 8.31 (1H, s), 10.00 (1H, s).

EXAMPLE 199N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-phenylpyrazole-4-carboxamide⅔ hydrate

By the reaction and treatment in the same manner as in Example 64 using5-methyl-1-phenylpyrazole-4-carboxylic acid (0.5 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(0.7 g), the title compound (0.8 g) was obtained, melting point: 227° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, dq, J=3.5, 11.7 Hz),1.75(2H, d, J=13.7 Hz), 2.45–2.50 (1H, m), 2.55 (3H, s), 2.67 (4H, m),3.11 (4H, m), 3.29 (2H, d, J=11.7 Hz), 3.90 (2H, d, J=7.8 Hz), 7.19 (1H,d, J=8.8 Hz), 7.39–7.70 (5H, m), 7.85 (1H, dd, J=2.5, 8.8 Hz), 8.09 (1H,d, J=2.5 Hz), 8.29 (1H, s), 9.99 (1H, s).

EXAMPLE 2001-(3-Chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (0.8 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(1.0 g), the title compound (0.7 g) was obtained, melting point: 230° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, ddd, J=3.9, 11.2, 11.7 Hz),1.75 (2H, d, J=13.7 Hz), 2.42–2.45 (1H, m), 2.50 (3H, s), 2.67 (4H, m),3.10 (4H, m), 3.28 (2H, d, J=11.7 Hz), 3.90 (2H, d, J=11.2 Hz), 7.19(1H, d, J=9.2 Hz), 7.55–7.58 (3H, m), 7.59 (1H, s), 7.86 (1H, d, J=2.4,9.2 Hz), 8.09 (1H, d, J=2.4 Hz), 8.32 (1H, s), 10.01 (1H, s).

EXAMPLE 201N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methyl-1-(4-methylphenyl)pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile(0.9 g), the title compound (0.7 g) was obtained, melting point: 258° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.43 (2H, dq, J=3.9, 12.2 Hz), 1.75(2H, d, J=12.2 Hz), 2.40 (3H, s), 2.40–2.55 (1H, m), 2.55 (3H, s), 2.67(4H, m), 3.10 (4H, m), 3.27 (2H, d, J=11.7 Hz), 3.90 (2H, d, J=7.8 Hz),7.18 (1H, d, J=9.3 Hz), 7.36 (2H, d, J=8.3 Hz), 7.41 (2H, d, J=8.3 Hz),7.86 (1H, dd, J=2.4, 9.3 Hz), 8.09 (1H, d, J=2.4 Hz), 8.27 (1H, s), 9.97(1H, s).

EXAMPLE 2021-(4-Chlorophenyl)-N-{3-cyano-4-[4-(3,4,5,6-tetrahydro-2H-thiopyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 64 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.3 g) and5-amino-2-[4-(3,4,5,6-tetrahydro-2H-thiopyran-4-yl)piperazin-1-yl]benzonitrile (1.1 g), the title compound (1.1 g) wasobtained, melting point: 281° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.58–1.68 (2H, m), 2.07 (2H, d, J=12.2Hz), 2.41–2.50 (1H, m), 2.56 (3H, s), 2.65 (2H, d, J=11.7 Hz), 2.68 (4H,m), 3.09 (4H, m), 3.33 (2H, m), 7.18 (1H, d, J=8.8 Hz), 7.60 (2H, d,J=8.8 Hz), 7.64 (2H, d, J=8.8 Hz), 7.85 (1H, dd, J=2.4, 8.8 Hz), 8.08(1H, d, J=2.4 Hz), 8.31 (1H, s), 10.00 (1H, s).

EXAMPLE 2031-(4-Chlorophenyl)-N-[3-cyano-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.8 g) and5-amino-2-[4-(2-methoxyethyl)piperazin-1-yl]benzonitrile (0.8 g), thetitle compound (0.7 g) was obtained, melting point: 207° C.

EXAMPLE 2041-(4-Chlorophenyl)-N-[3-cyano-4-[4-(4-methoxypiperidin-1-yl)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.4 g) and5-amino-2-[4-(4-methoxypiperidin-1-yl)piperidin-1-yl]benzonitrile (0.5g), the title compound (0.2 g) was obtained, melting point: 245° C.decomposition.

EXAMPLE 2051-(4-Chlorophenyl)-N-[3-cyano-4-[4-(4-oxopiperidin-1-yl)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide¼ hydrate

To a solution of oxalyl chloride (0.1 ml) and dimethyl sulfoxide (0.2ml) in methylene chloride (30 ml) were added under ice-cooling1-(4-chlorophenyl)-N-[3-cyano-4-[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamidesynthesized in Example 189 and triethylamine (0.9 ml), and the mixturewas stirred at the same temperature for 1 h. To a reaction mixture wasadded aqueous sodium hydroxide solution. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (mobile phase:chloroform:methanol=20:1) to give the title compound (0.2 g), meltingpoint: 213° C.

EXAMPLE 2061-(4-Chlorophenyl)-N-[3-cyano-4-(3-morpholinopropoxy)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.74 g) and5-amino-2-(3-morpholinopropoxy) benzonitrile (0.76 g), the titlecompound (0.35 g) was obtained, melting point: 155–157° C.

¹H-NMR (400 MHz, DMSO-dr) δ(ppm): 1.9–1.95 (2H, m), 2.3–2.4 (4H, m),2.4–2.5 (2H, m), 2.56 (3H, s), 3.55–3.6 (4H, m), 4.17 (2H, t, J=6.3 Hz),7.28 (1H, d, J=9.2 Hz), 7.60 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.8 Hz),7.90 (1H, dd, J=2.4, 9.2 Hz), 8.07 (1H, d, J=2.4 Hz), 8.31 (1H, s),10.00 (1H, s)

EXAMPLE 207 N-[3-Cyano-4-(3-morpholinopropoxy)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (1.0g) synthesized according to Starting Material Synthesis Example 88 and5-amino-2-(3-morpholinopropoxy)benzonitrile (0.9 g), the title compound(0.75 g) was obtained, melting point: 172–174° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.9–1.95 (2H, m), 2.3–2.4 (4H, m),2.4–2.5 (2H, m), 2.63 (3H, s), 3.55–3.6 (4H, m), 4.17 (2H, t, J=6.3 Hz),7.29 (1H, d, J=9.3 Hz), 7.84 (2H, d, J=8.3 Hz), 7.90 (1H, dd, J=2.5, 9.3Hz), 7.95 (2H, d, J=8.3 Hz), 8.07 (1H, d, J=2.5 Hz), 8.36 (1H, s), 10.04(1H, s)

EXAMPLE 2081-(4-Chlorophenyl)-N-[3-cyano-4-(2-morpholinoethoxy)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.65 g) and5-amino-2-(2-morpholinoethoxy)benzonitrile (0.95 g), the title compound(1.02 g) was obtained, melting point: 187–189° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 2.5–2.6 (4H, m), 2.56 (3H, s), 2.7–2.8(2H, m), 3.5–3.6 (4H, m), 4.25 (2H, t, J=5.4 Hz), 7.30 (1H, d, J=9.2Hz), 7.60 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.8 Hz), 7.90 (1H, dd,J=2.4, 9.2 Hz), 8.07 (1H, d, J=2.4 Hz), 8.31 (1H, s), 10.00 (1H, s)

EXAMPLE 209N-[3-Cyano-4-(2-morpholinoethoxy)phenyl]-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.74g) synthesized according to Starting Material Synthesis Example 88 and5-amino-2-(2-morpholinoethoxy)benzonitrile (0.95 g), the title compound(0.78 g) was obtained, melting point: 191–193° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 2.5–2.6 (4H, m), 2.73 (3H, s), 2.7–2.8(2H, m), 3.5–3.6 (4H, m), 4.25 (2H, t, J=5.3 Hz), 7.31 (1H, d, J=9.3Hz), 7.84 (2H, d, J=8.3 Hz), 7.90(1H, dd, J=2.9, 9.3 Hz), 7.95 (2H, d,J=8.3 Hz), 8.07 (1H, d, J=2.9 Hz), 8.36 (1H, s), 10.05 (1H, s)

EXAMPLE 2101-(4-Chlorophenyl)-N-[3-cyano-4-((4-morpholinopiperidin-1-yl)methyl)phenyl]-5-methylpyrazole-4-carboxamide

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.26 g) and5-amino-2-((4-morpholinopiperidin-1-yl)methyl)benzonitrile (0.3 g), thetitle compound (0.16 g) was obtained, melting point: 167–168° C.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.3–1.4 (2H, m), 1.7–1.8 (2H, m),1.95–2.05 (2H, m), 2.1–2.2 (1H, m), 2.4–2.5 (4H, m), 2.57 (3H, s),2.8–2.9 (2H, m), 3.5–3.6 (6H, m), 7.53 (1H, d, J=8.8 Hz), 7.61 (2H, d,J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz), 7.93 (1H, d, J=8.8 Hz), 8.18 (1H, s),8.34 (1H, s), 10.14 (1H, s)

EXAMPLE 2111-(4-Chlorophenyl)-N-[3-cyano-4-(3-hydroxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 150 using1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (3.9 g) and5-amino-2-(3-hydroxypropylthio)benzonitrile (2.9 g), the title compound(1.5 g) was obtained, melting point: 165° C.

EXAMPLE 2121-(4-Chlorophenyl)-N-[3-cyano-4-(3-morpholinopropylthio)phenyl]-5-methylpyrazole-4-carboxamide

A solution of1-(4-chlorophenyl)-N-[3-cyano-4-(3-hydroxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide(1.8 g) and methanesulfonyl chloride (0.5 ml) in pyridine (20 ml) wasstirred overnight. To the reaction mixture was added aqueoushydrochloric acid solution and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(mobile phase: chloroform:methanol=50:1) to give1-(4-chlorophenyl)-N-[3-cyano-4-(3-methanesulfonyloxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide(1.2 g).

The above compound (0.6 g) and morpholine (0.5 g) were stirred indimethylformamide (20 ml) at room temperature for 2 h. To the reactionmixture was added aqueous sodium hydroxide solution and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate. The mixture was acidified with hydrochloric acid-ethanol andcrystals were precipitated. The crystals were added to ethyl acetate andaqueous sodium hydroxide solution again, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was recrystallized from a mixedsolvent of ethyl acetate and hexane to give the title compound (0.2 g),melting point: 105–110° C. (decomposition)

EXAMPLE 2131-(4-Chlorophenyl)-N-[3-cyano-4-(3-piperidinopropylthio)phenyl]-5-methylpyrazole-4-carboxamide¼ hydrate

By the reaction and treatment in the same manner as in Example 212 usingpiperidine instead of morpholine, the title compound was obtained,melting point: 142° C.

In the same manner as in the above-described Starting Material SynthesisExamples and Examples, the following compound can be produced.

EXAMPLE 2141-(4-Chlorophenyl)-N-[3-cyano-4-(morpholinomethoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2151-(4-Fluorophenyl)-N-[3-cyano-4-(morpholinomethoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2161-(4-Fluorophenyl)-N-[3-cyano-4-(2-morpholinoethoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2171-(4-Fluorophenyl)-N-[3-cyano-4-(3-morpholinopropoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2181-(4-Fluorophenyl)-N-[3-cyano-4-(4-morpholinobutoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2191-(4-Chlorophenyl)-N-[3-cyano-4-(4-morpholinobutoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2201-(4-Fluorophenyl)-N-[3-cyano-4-(morpholinomethylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2211-(4-Fluorophenyl)-N-[3-cyano-4-(2-morpholinoethylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2221-(4-Fluorophenyl)-N-[3-cyano-4-(3-morpholinopropylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2231-(4-Fluorophenyl)-N-[3-cyano-4-(4-morpholinobutylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2241-(4-Chlorophenyl)-N-[3-cyano-4-(morpholinomethylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2251-(4-Chlorophenyl)-N-[3-cyano-4-(2-morpholinoethylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2261-(4-Chlorophenyl)-N-[3-cyano-4-(3-morpholinopropylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2271-(4-Chlorophenyl)-N-[3-cyano-4-(4-morpholinobutylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2281-(4-Chlorophenyl)-N-[3-cyano-4-(2-(4-morpholinopiperidin-1-yl) ethyl)phenyl]-5-ethylpyrazole-4-carboxamide EXAMPLE 2291-(4-Chlorophenyl)-N-[3-cyano-4-(3-(4-morpholinopiperidin-1-yl)propyl)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2301-(4-chlorophenyl)-N-[3-cyano-4-(4-(4-morpholinopiperidin-1-yl)butyl)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2311-(4-Trifluoromethylphenyl)-N-[3-cyano-4-(morpholinomethoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2321-(4-Trifluoromethylphenyl)-N-[3-cyano-4-(2-morpholinoethoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2331-(4-trifluoromethylphenyl)-N-[3-cyano-4-(3-morpholinopropoxy)phenyl]-5]ethylpyrazole-4-carboxamideEXAMPLE 2341-(4-Trifluoromethylphenyl)-N-[3-cyano-4-(4-morpholinobutoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2351-(4-Trifluoromethylphenyl)-N-[3-cyano-4-(morpholinomethylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2361-(4-Trifluoromethylphenyl)-N-[3-cyano-4-(2-morpholinoethylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2371-(4-trifluoromethylphenyl)-N-[3-cyano-4-(3-morpholinopropylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2381-(4-Trifluoromethylphenyl)-N-[3-cyano-4-(4-morpholinobutylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 239N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-trifluoromethylphenyl)pyrrole-3-carboxamideEXAMPLE 240N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)pyrrole-3-carboxamideEXAMPLE 241N-(3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(3,4-dichlorophenyl)pyrrole-3-carboxamideEXAMPLE 242N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dichlorophenyl)pyrrole-3-carboxamideEXAMPLE 2431-(4-Chlorophenyl)-N-{3-ethynyl-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamideEXAMPLE 2441-(4-Chlorophenyl)-5-methyl-N-{3-(1-propyne)-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}pyrazole-4-carboxamideEXAMPLE 2451-(4-Chlorophenyl)-5-methyl-N-[3-(1-propyne)-4-(4-morpholinopiperidin-1-yl)phenyl]pyrazole-4-carboxamideEXAMPLE 2461-(4-Chlorophenyl)-N-(3-ethenyl-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-5-methylpyrazole-4-carboxamideEXAMPLE 2471-(4-Chlorophenyl)-N-[3-ethenyl-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 248 1-(4-Chlorophenyl)-N-[3-iodo-4-(4-morpholinopiperidin-115yl) phenyl]-5-methylpyrazole-4-carboxamide EXAMPLE 249N-{3-Bromo-4-[4-(3,4,5,6-tetrahydro-2H-pyran-420yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 250 N-{3-Chloro-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)_(p)-5-methylpyrazole-4-carboxamideEXAMPLE 251N-{3-Chloro-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)pyrrole-3-carboxamideEXAMPLE 252 N-{3-Bromo-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}-1-(4-chlorophenyl)pyrrole-3-carboxamide EXAMPLE2531-(4-Chlorophenyl)-N-[3-cyano-4-(5-morpholinopentyloxy)phenyl]β-5-methylpyrazole-4-carboxamideEXAMPLE 2541-(4-Chlorophenyl)-N-[3-cyano-4-(5-morpholinopentyloxy)phenyl]pyrrole-3-carboxamide EXAMPLE 2551-(4-Chlorophenyl)-N-[3-cyano-4-(5-morpholinopentylthio)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2561-(4-Chlorophenyl)-N-[3-cyano-4-(5-morpholinopentylthio)phenyl]pyrrole-3-carboxamideEXAMPLE 257N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 258N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 259N-(3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl)-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 260N-{3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 2611-(4-Chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-5-methylpyrazole-4-carboxamideEXAMPLE 2621-(4-Chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]pyrrole-3-carboxamideEXAMPLE 263N-[3-Cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-5-methyl-1-(3,4-methylenedioxyphenyl)pyrazole-4-carboxamideEXAMPLE 264N-[3-Cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 265N-[3-Cano-4-(4-morpholinopiperidin-1-yl)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 266N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 267N-[3-Cyano-4-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 268N-[3-Chloro-4-(4-morpholinopiperidin-1-yl)phenyl]-2,5-dimethyl-1-(3,4-methylenedioxyphenyl)pyrrole-3-carboxamideEXAMPLE 269N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-S-methylpyrazole-4-carboxamideEXAMPLE 270N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)pyrrole-3-carboxamideEXAMPLE 271N-[3-Cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2,5-dimethylpyrrole-3-carboxamideEXAMPLE 2721-(4-Chlorophenyl)-N-[3-cyano-4-(2,2-dimethyl-3-morpholinopropoxy)phenyl]-2,5-dimethylpyrrole-3-carboxamideEXAMPLE 2731-(4-Chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperazin-1-yl)phenyl]-2,5-dimethylpyrrole-3-carboxamideEXAMPLE 274N-{3-Cyano-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 2751-(4-Chlorophenyl)-N-(3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamideEXAMPLE 276N-[4-(Piperidin-4-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 277N-[4-(1-Methylpiperidin-4-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 278N-[4-(1-Benzylpyrrolidin-3-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 279N-[4-(3,4,5,6-Tetrahydro-2H-pyran-4-yloxy)-3-cyanophenyl]-1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 280N-[4-(2,3,4,5-Tetrahydrofuran-3-yloxy)-3-cyanophenyl]-1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxamideEXAMPLE 281N-[4-(Piperidine-4-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)pyrrole-3-carboxamideEXAMPLE 282N-[4-(1-Methylpiperidin-4-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)pyrrole-3-carboxamideEXAMPLE 283N-[4-(1-Benzylpyrrolidin-3-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)pyrrole-3-carboxamideEXAMPLE 284N-[4-(3,4,5,6-Tetrahydro-2H-pyran-4-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)pyrrole-3-carboxamide EXAMPLE 285N-[4-(2,3,4,5-Tetrahydrofuran-3-yloxy)-3-cyanophenyl]-1-(4-chlorophenyl)pyrrole-3-carboxamideFORMULATION EXAMPLE

(mg) compound of the present invention 10.0 lactose 109.6microcrystalline cellulose 27.4 light anhydrous silicic acid 1.5magnesium stearate 1.5 150 (per tablet)

The compound of the present invention (30 g), lactose (328.8 g) andmicrocrystalline cellulose (82.2 g) are mixed. The mixture iscompression formed with a roller compactor to give compressed flakes.The compressed flakes are pulverized in a hammer mill and thepulverizate is passed through a 20-mesh sieve. To the resulting productare added light anhydrous silicic acid (4.5 g) and magnesium stearate(4.5 g), followed by admixing. The mixture is punched with a 7.5 mmdiameter pounder to give 3000 tablets weighing 150 mg per tablet.

As regards the pharmacological activity of the compound of the presentinvention and a pharmaceutically acceptable salt thereof, in vitroproliferation reaction of mouse, rat, dog, monkey or human lymphocytesactivated with antigen or mitogen, lymphocyte proliferation reactiondependent on cytokine (e.g., IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 andthe like), or production of inflammatory cytokine (e.g., TNF-α, IL-1,IL-6, IL-12, IL-15, IL-18 and the like) derived by lymphocytes,macrophages, dendritic cells and the like upon addition of IL-15,lipopolysaccharide and the like can be tested for evaluation ofinhibitory activity. The compound of the present invention and apharmaceutically acceptable salt thereof show an inhibitory effect inthe above-mentioned in vitro test at a concentration of 0.001–100 μMwhich is significant as compared to a control group without addition ofthe compound.

For the in vivo pharmacological activity of the compound of the presentinvention or a pharmaceutically acceptable salt thereof, type IIcollagen-induced arthritis is used, which is induced by immunizing amouse, rat, dog or monkey with type II collagen derived from bovine orsuitable mammal together with Freund's complete adjuvant. To bespecific, the compound of the present invention or a pharmaceuticallyacceptable salt thereof is intravenously, intraperitoneally,subcutaneously or orally administered and the inhibitory activity isevaluated. Besides the above-mentioned test, similar evaluation ispossible with regard to an autoimmune disease model such as a rat ormouse model with adjuvant arthritis, experimental cerebral meningitisand the like. Using MRL/MpJ-lpr/lpr mouse, (NZBxNZW)F1 mouse and BXSBmouse that spontaneously develop autoimmune diseases similar to systemiclupus erythematosus in human, the therapeutic effect of the compound ofthe present invention and a pharmaceutically acceptable salt thereofagainst autoimmune diseases can be evaluated based on manifestation ofproteinuria in lupus erythematosus nephritis, production amount ofanti-autoantibody such as anti-DNA antibody, rheumatoid factor,anti-erythrocyte antibody, anti-type II collagen antibody and the like,infiltration of activated lymphocytes into inflammation site andproliferation thereof, survival days and the like, as indices. Thecompound of the present invention and a pharmaceutically acceptable saltthereof show a significant inhibitory effect or therapeutic effect ascompared to a control group with medium administration alone, byintravenous, intraperitoneal, subcutaneous or oral administration at0.1–100 mg/kg body weight in the above-mentioned in vivo pharmacologicaltest. The following Experimental Examples detail such aspect.

EXPERIMENTAL EXAMPLE 1 Effect on Proliferation of Rat LymphocytesStimulated with Phorbol-12-Myristate-13-Acetate (PMA) and CalciumIonophore A23187

As the medium, RPMI1640 medium (Sigma) supplemented with kanamycinsulfate (60 μg/ml) and penicillin G potassium (100 unit/ml), and fetalcalf serum (FCS, Gibco), that underwent inactivation treatment at 56° C.for 30 min, in a proportion of 10% was used for the test. The compoundof the present invention or a pharmaceutically acceptable salt thereofwas dissolved in dimethyl sulfoxide, diluted with 10% FCS-containingRPMI1640 medium to a desired concentration and used for the test.

Spleen was aseptically removed from 6-week-old male F344 rat or LEW rat(Charles River Japan) and broken up in the RPMI1640 medium withtweezers, after which a single cell suspension of spleen cells wasprepared. After haemolysis by hypotonic treatment using a mixture of0.83% aqueous ammonium chloride solution and Tris-HCl buffer at pH 7.65at a mixing ratio of 9:1, it was passed through a nylon-wool column togive a nylon non-adhering T cell condensed fraction. A cell suspensionprepared using a 10% FCS-containing RPMI1640 medium was added to aflat-bottomed 96 well microtest plate at 5×10⁵ cells/well. The compoundof the present invention or a pharmaceutically acceptable salt thereofhaving a concentration of 0.0001–100 μM, 10 ng/ml of PMA and 100 ng/mlof A23187 were added and the mixture was cultured at 37° C., under 5%CO₂, 95% air for 44 h. After the completion of the culture, tritiatedthymidine (specific activity:185 GBq/mmol, Amersham Pharmacia Biotec)was added at 18.5 kBq/well and the mixture was cultured further at 37°C., under 5% CO₂, 95% air for 4 h. Then, using a cell harvester, thecells were recovered on a glass fiber filter, and using a platescintillation counter (Microbeta 1460), the radioactivity taken into thecells was measured, based on which the proliferation of rat lymphocytesinduced by the stimulation with PMA and A23187 was determined. That is,percent of inhibition was calculated from the following formula from theaverage of tritiated thymidine uptake (cpm) into the lymphocytes in thewell added with various concentrations of the compound of the presentinvention.${{Inhibition}\mspace{14mu}(\%)} = {1 - {\left( \frac{{radioactivity}\mspace{14mu}({cpm})\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{with}\mspace{14mu}{compound}}{{radioactivity}\mspace{14mu}({cpm})\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{without}\mspace{14mu}{compound}} \right) \times 100}}$

In addition, the concentration (IC₅₀) of the compound at which thecompound inhibits the radioactivity to 50% of the value of the controlgroup was determined by nonlinear regression based on the dose reactioncurve obtained by plotting the average of tritiated thymidine uptake(cpm) or percent of inhibition on the axis of ordinates and theconcentration on the axis of abscissas.

The compound of the present invention and a pharmaceutically acceptablesalt thereof showed a significant and concentration-dependent inhibitoryeffect in the above-mentioned in vitro test, as compared to the controlgroup without addition of the compound.

EXPERIMENTAL EXAMPLE 2 Effect on IL-2, IL-4, IL-7, IL-9, IL-13 orIL-15-Dependent Proliferation of IL-2-Dependent Mouse CTL-2 Cell,D10.G4.1 cell and HT2 cell.

As the medium, RPMI1640 medium (Sigma) supplemented with kanamycinsulfate (60 μg/ml) and penicillin G potassium (100 unit/ml), and fetalcalf serum (FCS, Gibco), that underwent inactivation treatment at 56° C.for 30 min, in a proportion of 10% was used for the test. The compoundof the present invention or a pharmaceutically acceptable salt thereofwas dissolved in dimethyl sulfoxide, diluted with 10% FCS-containingRPMI1640 medium to a desired concentration and used for the test.

Using IL-2-dependent mouse CTLL-2 cell, D10.G4.1 cell or HT2 cell(purchased from American Type Culture Collection), proliferationdependent on IL-2, IL-4, IL-7, IL-9, IL-13 or IL-15 was measured usingtritiated thymidine uptake into the cells as an index.

The CTLL-2 cell, D10.G4.1 cell or HT2 cell was adjusted to aconcentration of 10⁵ cells/ml using an RPMI1640 medium containing 10%FCS and 5×10⁻⁵ M of 2-mercaptoethanol, and dispensed to a 96 wellmicrotest plate at 10⁴ cells/well. 0.01–10 ng/ml of recombinant human,monkey or mouse IL-2, IL-4, IL-7, IL-9, IL-13 or IL-15 (Genzyme/Techne)and the compound of the present invention or a pharmaceuticallyacceptable salt thereof having a concentration of 0.0001–100 μM wereadded, and the mixture was cultured at 37° C., under 5% CO₂, 95% air for20–92 h. After the completion of the culture, tritiated thymidine(specific activity:185 GBq/mmol, Amersham Pharmacia Biotec) was added at18.5 kBq/well and the mixture was cultured at 37° C., under 5% CO₂, 95%air for 4 h. Then, using a cell harvester, the cells were recovered on aglass fiber filter, and using a plate scintillation counter (Microbeta1460), the radioactivity taken into the cells was measured, and T cellproliferation dependent on IL-2, IL-4, IL-7, IL-9, IL-13 or IL-15 wasmeasured. That is, percent of inhibition was calculated from thefollowing formula from the average of tritated thymidine uptake (cpm)into the lymphocytes in the well added with various concentrations ofthe compound of the present invention.${{Inhibition}\mspace{14mu}(\%)} = {1 - {\left( \frac{{radioactivity}\mspace{14mu}({cpm})\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{with}\mspace{14mu}{compound}}{{radioactivity}\mspace{14mu}({cpm})\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{without}\mspace{14mu}{compound}} \right) \times 100}}$

In addition, the concentration (IC₅₀) of the compound at which thecompound inhibits the radioactivity to 50% of the value of the controlgroup was determined by nonlinear regression based on the dose reactioncurve obtained by plotting the average of tritated thymidine uptake(cpm) or percent of inhibition on the axis of ordinates and theconcentration on the axis of abscissas.

The compound of the present invention and a pharmaceutically acceptablesalt thereof showed a significant and concentration-dependent inhibitoryeffect in the above-mentioned in vitro test, as compared to the controlgroup without addition of the compound.

EXPERIMENTAL EXAMPLE 3 Effect on Production of IL-1, IL-6, IL-12, IL-15,IL-18, TNF-α by Mouse Macrophage or Macrophage-Like Cell Line J774A.1Cell

As the medium, RPMI1640 medium (Sigma) supplemented with kanamycinsulfate (60 μg/ml) and penicillin G potassium (100 unit/ml), and fetalcalf serum (FCS, Gibco), that underwent inactivation treatment at 56° C.for 30 min, in a proportion of 10% was used for the test. The compoundof the present invention or a pharmaceutically acceptable salt thereofwas dissolved in dimethyl sulfoxide, diluted with 10% FCS-containingRPMI1640 medium to a desired concentration and used for the test.

To 7-week-old male C57BL/6 mouse (Charles River Japan) wasintraperitoneally administered a 10% proteous peptone (Difco) solution,and intraperitoneally infiltrated cells were harvested 4 days later. Thecells were incubated in a 24 well plate for 1 h and, after removing thefloating cells, used as macro phages. To the single cell layer(monolayer) of the macrophage obtained above or mouse macrophage-likecell line J774A.1(purchased from American Type Culture Collection) wereadded 0.1–10 μg/ml of lipopolysaccharide (Difco) or 0.01–10 ng/ml ofrecombinant human, monkey or mouse IL-15 (Genzyme) and the compound ofthe present invention or a pharmaceutically acceptable salt thereofhaving a concentration of 0.0001–100 μM and the mixture was cultured at37° C., under 5% CO₂, 95% air for 12–96 h. After the completion of theculture, the culture supernatant was recovered and IL-1, IL-6, IL-12,IL-15, IL-18, TNF-α produced in the supernatant was quantitativelymeasured by an enzyme-linked immunosorbent assay (ELISA), and theinhibitory effect of cytokine production was evaluated. The activity ofIL-1, IL-6, IL-12, IL-15, IL-18, TNF-α produced in the supernatant wasalso evaluated by a bioassay using the dependent cells line. The totalRNA in the cells was recovered and mRNA of the cytokine was amplified byreverse transcriptase-polymerase chain reaction (RT-PCR). The expressionof various cytokine mRNAs was semi-quantitatively determined usinghypoxanthine-guanine phosphoribosyltransferase as the control mRNA andused as an index of cytokine production. That is, percent of inhibitionwas calculated from the following formula from the average of cytokineproduction or mRNA expression when various concentrations of thecompound of the present of invention was added.${{Inhibition}\mspace{14mu}(\%)} = {1 - {\left( \frac{{cytokine}\mspace{14mu}{production}\mspace{14mu}{with}\mspace{14mu}{compound}}{{cytokine}\mspace{14mu}{production}\mspace{14mu}{without}\mspace{14mu}{compound}} \right) \times 100}}$

In addition, the concentration (IC₅₀) of the compound, at which thecompound inhibits the cytokine production to 50% of the value of thecontrol group, was determined by nonlinear regression based on the dosereaction curve obtained by plotting the average of cytokine productionor percent of inhibition on the axis of ordinates and the concentrationon the axis of abscissas.

The compound of the present invention and a pharmaceutically acceptablesalt thereof showed a significant and concentration-dependent inhibitoryeffect in the above-mentioned in vitro test, as compared to the controlgroup without the addition of the compound.

EXPERIMENTAL EXAMPLE 4 Effect on JAK Phosphorylation

The CTLL-2 cell, D10.G4.1 cell or HT-2 cell, which is a mouse T cellsline, was cultured in the presence of a recombinant simian IL-15 orrecombinant mouse IL-2 for 24 h. A lysate of the cell obtained by theaddition of buffer for lysis was mixed with anti-JAK3 antibody (UBI) oranti-JAK1 antibody (SantaCruz) and a protein agarose, and stirred at 4°C. for 2 h for immunoprecipitation. The immunoprecipitated protein waselectrophoresed on 7.5% SDS polyacrylamide gel, transferred onto PVDFmembrane filter and subjected to western blotting. That is, afterblocking with skim milk, blotting with anti-phosphothyrosine antibody(4G10, UBI), and addition of peroxidase labeled anti-immunoglobulinantibody and substrate for color development were performed to detect aband.

It was clarified that the compound of the present invention or apharmaceutically acceptable salt thereof inhibited phosphorylation ofJAK1 or JAK3 in a concentration-dependent manner in the above-mentionedin vitro test.

EXPERIMENTAL EXAMPLE 5 Effect on Type II Collagen Induced Arthritis inDBA/1J Mouse

An emulsion was prepared by mixing bovine type II collagen (100–200 μg,purchased from Collagen Gizyutsu Kensyukai) with Freund's completeadjuvant (Sigma) containing dead tubercle bacillus H37Ra was given to6–7 week-old male DBA/1J mice (Charles River Japan) subcutaneously fromthe root of the tail for immunization twice at 3 week intervals, therebydeveloping arthritis. The compound of the present invention or apharmaceutically acceptable salt thereof was suspended or dissolved in0.5% hydroxypropylmethylcellulose and orally administered repeatedly atthe dose of 0.01–100 mg/kg body weight using an oral sound for 6 weeksfrom the first immunization. This model was evaluated for the symptomsof arthritis in the four limbs according to the following criteria in 0to 4 scores. The arthritis score of each mouse was expressed by thetotal of the scores of the four limbs (maximum:16 points), and when thetotal score was 1 or more, the onset of arthritis was acknowledged.

score Symptom 0 No change 1 edema in only one joint 2 edema in two ormore joints (light edema of whole limb) 3 severe edema of whole limb 4severe edema of whole limb and rigid and immobilized joint

The thickness of the four limbs of the mouse was measured with verniercalipers and the total score of the four limbs was used as an index ofarthritis. Using a soft X-ray photography (OHMIC co.), the four limbswere X rayed to evaluate the level of destruction of the joints.

The score of arthritis, the total of thickness of the four limbs andjoint destruction score were expressed by average and standard error ofeach group (n=5–10). Using the group administered with medium alone as acontrol, statistical analysis was performed by the non-parametric orparametric Dunnett's method, wherein p value of not more than 0.05 wasconsidered significant.

The compound of the present invention or a pharmaceutically acceptablesalt thereof was clarified to have shown significant and dose-dependentimprovement in severity of arthritis, swelling of four limbs and jointdestruction, and strikingly inhibited the onset and progress ofarthritis in the above-mentioned in vivo test by repeat oraladministration at 0.1–100 mg/kg body weight, as compared to the controlgroup administered with medium alone.

In contrast,1-(4-fluorophenyl)-N-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamidedescribed in Bioorganic and Medicinal Chemistry Letters, vol. 8, pp.2787–2792 (1998) did not improve the severity of developed arthritis,swelling of four limbs or joint destruction by repeat oraladministration at 10 mg/kg body weight, and death incidence wasconfirmed by repeat oral administration at 30 mg/kg body weight.

EXPERIMENTAL EXAMPLE 6 Effect on Lupus Nephritis in SpontaneouslyDeveloping Systemic Lupus Erythematosus Model MRL/MpJ-lpr/lpr Mouse andLife Prolonging Effect

To male 8–16 week-old MRL/MpJ-lpr/lpr mice (Charles River Japan) wasrepeat orally administered every day, using an oral sound, 0.01–100mg/kg body weight of the compound of the present invention or apharmaceutically acceptable salt thereof suspended or dissolved in 0.5%hydroxypropylmethylcellulose. The survival rate during theadministration period was recorded and the blood and urine were sampledwith the lapse of time to measure plasma anti-nucleic antibody titer,rheumatoid factor and urinary protein amount. The compound of thepresent invention and a pharmaceutically acceptable salt thereof wereclarified to have shown marked decrease in the manifestation ofproteinuria and protein concentration in urine and suppression of theonset of lupus nephritis and improvement of symptoms in MRL/MpJ-lpr/lprmouse in the above-mentioned in vivo test by repeat oral administrationat 0.1–100 mg/kg body weight. In addition, the compound of the presentinvention and a pharmaceutically acceptable salt thereof were confirmedto have shown a life prolonging effect by a long-term administration toMRL/MpJ-lpr/lpr mouse.

EXPERIMENTAL EXAMPLE 7 Effect on Ovalbumin-Induced Mouse Biphasic EarEdema

Physiological saline (0.5 ml) containing ovalbumin (10 μg, Sigma) andaluminum hydroxide gel (1 mg) was used to immunize 6–7 week-old maleBALB/c mice (Charles River Japan) by intraperitoneally administeringtwice at 2 week intervals. One week later, ovalbumin (10 μg) wassubcutaneously injected to the ear lobe of the mice for a challenge,thereby inducing biphasic ear edema accompanying a biphasic at one hourand 24 hours after the challenge. The compound of the present inventionor a pharmaceutically acceptable salt thereof was suspended or dissolvedin 0.5% hydroxypropylmethylcellulose and repeat orally administered for3 weeks from the first immunization at a dose of 0.01–100 mg/kg bodyweight using an oral sound. The thickness of the ear lobe of the modelmice was measured with a dial gauge and used as an index of ear edema.

The thickness of the ear lobe was expressed in average and standarderror of each group (n=5–10), and using a group administered with amedium as a control, statistical analysis was performed by the Dunnett'smethod, wherein p value of not more than 0.05 was consideredsignificant.

The compound of the present invention and a pharmaceutically acceptablesalt thereof inhibited the induction of both early phase edema at onehour from the challenge and late phase edema at 24 hours from thechallenge significantly and dose-dependently in the above-mentioned invivo test, by repeat oral administration at 0.1–100 mg/kg body weight,as compared to the control group administered with medium alonesuggesting inhibition of allergic reaction involving type 2 helper Tcells.

EXPERIMENTAL EXAMPLE 8 Inhibitory Effect on Rat Experimental AutoimmuneCerebral Meningitis

An emulsion (0.1 ml) was prepared by mixing myelin basic protein (100μg, Sigma) with Freund's complete adjuvant (Sigma) containing deadtubercle bacillus H37Ra and given to immunize 6 week-old female LEW ratintracutaneously from the footpad of the right hind limb. The physicalsign after immunization was evaluated according to the followingcriteria in 6 levels.

score Symptom 0 No symptom 1 Weak tail 2 Weak hind limb 3 Paralysis ofone hind limb 4 Paralysis of both hind limbs 5 incontinence or death

The compound of the present invention and a pharmaceutically acceptablesalt thereof were confirmed to have markedly inhibited the onset andprogress of autoimmune cerebral meningitis in the above-mentioned invivo test by repeat oral administration for 20 days at 0.1–100 mg/kgbody weight.

EXPERIMENTAL EXAMPLE 9 Combination Effect Test

According to the method of B. D. Kahan et al. [Transplantation, vol. 55,pp. 849–900 (1993)], test compounds (2 or more) were singly administeredrespectively. Based on the dose-reaction curve, the effect ofcombination group was calculated and the combination index wasdetermined. It was defined that, when the combination index was 1, itmeans additive effect, when the combination index was smaller than 1, itmeans a synergistic effect, and when the combination index was greaterthan 1, it means an antagonistic effect.

The compound of the present invention and a pharmaceutically acceptablesalt thereof were confirmed to show a synergistic effect in theabove-mentioned combination effect test when combined with one or morepharmaceutical agents selected from an antirheumatic drug, animmunosuppressive agent, a steroidal drug and a nonsteroidalanti-inflammatory drug, by which the combination index was smaller than1.

EXPERIMENTAL EXAMPLE 10 Toxicity Test

In the single administration toxicity test, the test compound wasadministered to female and male SD rats (3 rats/group) and beagle (1dog/group), and the toxicity by single administration was evaluatedusing the incidence of death, general condition and body weight asindices. In the repeat administration toxicity test, the test compoundwas repeat administered for 2 weeks to female and male SD rats (6rats/group) and female and male beagle (2 dogs/group), and the toxicityby repeat administration of the test compound was evaluated based on thegeneral condition, body weight, diet taken, haematological test,haemato-biochemical test, weight of organ and biopsy (inclusive ofhistopathological test) as indices.

EXPERIMENTAL EXAMPLE 11 Evaluation of Bioavailability in Rat

The test compound is intravenously and orally administered to male SDrats (4 per group) and blood is drawn with the lapse of time. The plasmadrug concentration is measured by high performance liquidchromatography. The bioavailability (BA) is calculated by the followingformula. $\frac{\begin{matrix}{{AUC}\mspace{14mu}{upon}\mspace{14mu}{oral}} \\{administration}\end{matrix}}{\begin{matrix}{{AUC}\mspace{14mu}{upon}\mspace{14mu}{intravenous}} \\{administration}\end{matrix}} \times \frac{\begin{matrix}{{Dose}\mspace{14mu}{of}\mspace{14mu}{intravenous}} \\{administration}\end{matrix}}{\begin{matrix}{{Dose}\mspace{14mu}{of}\mspace{14mu}{oral}} \\{administration}\end{matrix}} \times 100(\%)$

-   -   AUC: area under the plasma concentration-time curve

INDUSTRIAL APPLICABILITY

As is evident from the above-mentioned pharmacological tests, toxicitytest and the like, the compound of the present invention and apharmaceutically acceptable salt thereof show superior inhibitory effecton the proliferation of activated lymphocytes, particularly inhibitoryeffect on lymphocyte proliferation dependent on IL-2, IL-4, IL-7, IL-9,IL-13 or IL-15 and also inhibit production of IL-15 and inflamatorycytokines induced by IL-15. In addition, since a superior effect isshown in arthritis models and autoimmune disease models, they are usefulas agents for the prophylaxis or treatment of various autoimmunediseases.

This application is based on patent application Nos. 33367/1999 and198473/1999 filed in Japan, the contents of which are herebyincorporated by reference.

1. An amide compound of the formula

wherein R¹ is substituted aryl, R² and R³ are the same or different andeach is hydrogen or alkyl, Q is nitrogen atom, W is hydrogen or alkyl, Xis cyano, X′ is hydrogen, and Y is optionally substituted piperidino, ora pharmaceutically acceptable salt thereof.
 2. The amide compound ofclaim 1, which has the formula

wherein R¹ is substituted aryl, R² and R³ are the same or different andeach is hydrogen or alkyl, Q is nitrogen atom, W is hydrogen or alkyl, Xis cyano, Y is optionally substituted piperidino, or a pharmaceuticallyacceptable salt thereof.
 3. An amide compound selected from the groupconsisting ofN-(3-cyano-4-piperidinophenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-hydroxypiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-(3-cyano-4-piperidinophenyl)-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-[3-cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,N-(4-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-3-cyanophenyl)-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,1-(3,4-dichlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,1-(3-chloro-4-fluorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxamide,N-{4-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]-3-cyanophenyl}-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-{3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-5-methylpyrazole-4-carboxamide,1-(4-bromophenyl)-N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methylphenyl)-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-iodophenyl)-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-[3-cyano-4-(4-thiomorpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-[3-cyano-4-(4-methoxymethoxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-[3-cyano-4-[4-(2-methoxyethoxy)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide,N-{3-cyano-4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-1(4-fluorophenyl)-5-methylpyrazole-4-carboxamide,N-[3-cyano-(4-morpholinopiperidin-1-yl)phenyl]-5-methyl-1-(4-nitrophenyl)pyrazole-4-carboxamide,1-(3-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidino)phenyl]-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-5-methylpyrazole-4-carboxamide,andN-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-dimethoxyphenyl)-5-methylpyrazole-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising the amide compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 5. A method for the treatment of rheumatoidarthritis in a subject, which comprises administering an effectiveamount of the pharmaceutical composition of claim 4 to the subject.
 6. Acombination composition comprising an amide compound of the formula

wherein R¹ is substituted aryl, R² and R³ are the same or different andeach is hydrogen or alkyl, Q is nitrogen atom, W is hydrogen or alkyl, Xis cyano, X′ is hydrogen, and Y is optionally substituted piperidino, ora pharmaceutically acceptable salt thereof, and one or morepharmaceutical agents selected from an antirheumatic drug, animmunosuppressive agent, a steroidal drug and a nonsteroidalanti-inflammatory drug.
 7. The combination composition of claim 6,wherein the antirheumatic drug is selected from a gold compound,penicillamine, bucillamine, lobenzarit, actarit and salazosulfapyridine.8. The combination composition of claim 6, wherein the immunosuppressiveagent is selected from azathioprine, cyclophosphamide, methotrexate,brequinar sodium, deoxyspergualin, mizoribine, 2-morpholinoethylmycophenolate, cyclosporin, rapamycin, tacrolimus hydrate, leflunomide,OKT-3, anti TNF-α antibody, anti IL-6 antibody and FTY720.
 9. Thecombination composition of claim 6, wherein the steroidal drug isselected from prednisolone, methylprednisolone, dexamethasone andhydrocortisone.
 10. The combination composition of claim 6, wherein thenonsteroidal anti-inflammatory drug is selected from aspirin,indomethacin, indomethacin farnesil, diclofenac sodium, alclofenac,amfenac sodium, ibuprofen, ketoprofen, loxoprofen sodium, naproxen,pranoprofen, zaltoprofen, mefenamic acid, flufenamic acid, tolufenamicacid, phenylbutazone, ketophenylbutazone, piroxicam, tenoxicam andampiroxicam.
 11. A method for the treatment of atopic dermatitis in asubject, which comprises administering an effective amount of thepharmaceutical composition of claim 4 to the subject.
 12. An amidecompound selected from the group consisting of1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,1-(4-chlorophenyl)-N-[3-cyano-4-(4-hydroxypiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide,N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxamide,andN-[3-cyano-4-(4-morpholinopiperidino)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide.13. A method for the treatment of cerebral meningitis in a subject,which comprises administering an effective amount of the pharmaceuticalcomposition of claim 4 to the subject.
 14. A method for the treatment ofmultiple sclerosis in a subject, which comprises administering aneffective amount of the pharmaceutical composition of claim 4 to thesubject.
 15. A method for the treatment of systemic lupus erythematodesin a subject, which comprises administering an effective amount of thepharmaceutical composition of claim 4 to the subject.
 16. A method forthe treatment of lupus nephritis in a subject, which comprisesadministering an effective amount of the pharmaceutical composition ofclaim 4 to the subject.
 17. A method for the treatment of inflammatorybowel disease in a subject, which comprises administering an effectiveamount of the pharmaceutical composition of claim 4 to the subject. 18.A method for the treatment of psoriasis in a subject, which comprisesadministering an effective amount of the pharmaceutical composition ofclaim 4 to the subject.